Metabolic Syndrome - Drug ManagementChih-Hsing Wu, MD Body Composition, Obesity and Osteoporosis Research Center, Department of Family Medicine, NCKUH Definition of Metabolic Syndrome in.
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Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 2
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 3
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 4
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 5
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 6
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 7
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 8
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 9
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 10
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 11
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 12
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 13
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 14
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 15
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 16
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 17
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 18
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 19
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 20
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 21
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 22
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 23
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 24
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 25
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 26
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 27
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 28
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 29
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 30
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 31
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 32
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 33
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 34
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 35
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 36
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 37
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 38
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 39
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 40
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 41
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 42
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 43
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 44
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 45
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 46
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 47
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 48
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 49
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 50
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 51
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 52
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 53
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 54
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 55
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 56
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 57
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 58
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 59
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 60
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 61
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 62
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 63
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 64
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 65
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 66
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 67
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 68
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 69
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 70
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 2
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 3
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 4
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 5
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 6
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 7
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 8
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 9
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 10
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 11
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 12
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 13
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 14
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 15
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 16
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 17
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 18
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 19
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 20
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 21
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 22
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 23
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 24
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 25
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 26
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 27
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 28
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 29
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 30
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 31
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 32
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 33
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 34
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 35
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 36
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 37
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 38
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 39
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 40
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 41
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 42
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 43
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 44
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 45
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 46
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 47
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 48
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 49
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 50
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 51
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 52
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 53
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 54
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 55
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 56
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 57
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 58
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 59
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 60
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 61
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 62
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 63
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 64
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 65
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 66
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 67
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 68
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 69
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong
Slide 70
Metabolic Syndrome
- Drug ManagementChih-Hsing Wu, MD
Body Composition, Obesity and Osteoporosis Research
Center, Department of Family Medicine, NCKUH
Definition of Metabolic Syndrome in Taiwan
2007-01-18
修正前（臺灣2004年版）
危 險
因
子
異
常
修正後（臺灣2006年版）
值
危
險
因
子
異
常
值
腹部肥胖(Central
obesity) /或身體質量指
數（BMI）
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm ；或
BMI ≧27
腹部肥胖(Central
obesity)
腰圍（waist）:
男性 ≧90 cm
女性 ≧80 cm
血壓(BP)上升
SBP ≧130 mmHg
/DBP ≧85 mmHg
血壓(BP)上升
SBP ≧130 mmHg /DBP
≧85 mmHg
高密度酯蛋白膽固醇
(HDL-C)過低
男性 <40 mg/dl
女性 <50 mg/dl
高密度酯蛋白膽固
醇(HDL-C)過低
男性 <40 mg/dl；女性
<50 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧110 mg/dl
空腹血糖值(Fasting
glucose)上升
FG ≧100 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
三酸甘油酯
(Triglyceride)上升
TG ≧150 mg/dl
http://www.bhp.doh.gov.tw
代謝症候群臨床案例
•
•
•
•
•
60歲陳xx先生，有心血管疾病家族史
不抽煙，偶而應酬喝酒，週末爬山運動
身高168公分，體重70公斤，腰圍92(90)公分，體脂率28%
血壓136 / 86 (130/85) mmHg，心跳 72/min
抽血檢查
空腹血糖
105 mg/dl (100),
膽固醇
204 mg/dl,
三酸甘油脂
156 mg/dl (150),
高密度膽固醇
36 mg/dl (40),
尿酸值
8.1 mg/dl,
肌酸酐
1.1 mg/dl,
• 腹部超音波：中度脂肪肝
Metabolic Syndrome = Pre-Disease
Hyperglycemia
Hypertension
Dyslipidemia
Insulin Resistance
Risk Relative
To General Population
6
“Pre-diabetes”
5
Macrovascular
Disease
Type 2 Diabetes
Metabolic syndrome
4
3
2
Microvascular
Complications
1
0
-20
-15
-10
-5
0
5
Years of Diabetes
© 2001 International Diabetes Center. All rights reserved.
Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.
10
15
20
新陳代謝症候群個案的主要成份組
人數
佔新陳代謝症候群個案
(1023)之百分比
新陳代謝症候群
1023
100%
肥胖
852
83.3%
肥胖+高三酸甘油酯症
696
68.04%
肥胖+高三酸甘油酯症+高血壓
457
44.67%
肥胖+高三酸甘油酯症+高血壓+低
的高密度膽固醇
232
22.68%
CVD Risks and Anthropometric
Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
CVD Risks and Anthropometric
Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8
Obesity and Metabolic Syndrome:
A Cluster of Coronary Heart Disease Risk Factors
Obesity
Diet
Physical Inactivity
Stress
Raised
Blood Pressure
Genetic
Susceptibility
Prothrombotic
State
Atherogenic
Dyslipidemia
Triglycerides
High-Density
Lipoprotein Cholesterol
Insulin
Resistance
Small Low-Density
Lipoprotein Particles
Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:2595-2600.
Autonomic
Dysfunction
Proinflammatory
State
Obesity Is Strongly Associated with
Metabolic Syndrome NHANES III
Adjusted Odds Ratio
(± 95% CI)
1000
Men
Women
100
*
*
10
*
*
*
1
0.1
<18.5
18.5-24.9
25.0-29.9
30.0-34.5
Body Mass Index (kg/m2)
*P < .001 compared to BMI 18.5 to 24.9
Park YW, et al. Arch Intern Med. 2003;163:427-36.
35.0
*
肥胖的定義
身體質量指數=體重(公斤) 身高(公尺)2
世界衛生組織
亞太地區
台灣
亞太地區
過輕
1998
小於18.5
(2000)
小於18.5
2002
小於18.5
(2005)
小於18.5
正常
18.5~24.9
18.5~22.9
18.5~23.9
過重
25.0~29.9
23.0~24.9
24.0~26.9
肥胖 (第一度)
30.0~34.9
25.0~29.9
27.0~29.9
18.5~22.9
23.0~23.9
24.0~26.9
27.5~29.9
肥胖 (第二度)
35.0~39.9
30.0~34.9
30.0~34.9
30.0~34.9
肥胖 (第三度)
40以上
35以上
35以上
定義
35以上
減重16週前後代謝症候群的比例
Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4):220-23.
P<0.05*
0.4
0.35
比
例
0.3
0.25
0.2
0.15
0.1
0.05
0
＊配對T檢定
減重前
減重後
亞太肥胖治療建議
飲食控制 加強運動 藥物治療 極低熱量 手術治療
體重過重(23BMI25 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
肥胖 (25BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
過度肥胖 (BMI30 kg/m2)
無慢性病者
腰圍過粗
有慢性病者(糖尿病,高
血壓,高血脂,心臟病等)
Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346:591-602
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
羅氏鮮(Xenical)減重機轉
30% of
triglycerides
pass
undigested
and are
excreted.
羅氏鮮可減少食物中30%的脂肪攝取量
15
Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
Favours
Treatment
0
5
Favours
Control
10
•FDA advisory committee approval for a low dose (60 mg)
over-the-counter orlistat product (Alli) in 2007.
諾美婷(Reductil)的作用機轉
MAO
S
Reuptake
5-HT
RELEASE
S
MAO
S
Reuptake
NA
S = sibutramine
= noradrenaline,
= serotonin
Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
RELEASE
S
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
Favours
Treatment
0
5
Favours
Control
10
Sibutramine, Orlistat or Combination
Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
0
-2
-4
- 2 .5
- 3 .6
- 4 .4
- 5 .1
-6
- 6 .2
-8
- 9 .4
-10
-12
-14
- 8 .4
- 1 1.
BW
7
- 1 3. 5
-1 4
- 1 3.
WC
-16
-18
BMI
7
- 1 6. 7
Sibutramine
Orlistat
S+O
Diet
Similar Effects
The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH
the difference of measure
Low caloric diet
VLCD
Sibutramine
Orilstat
-2.5
-5.0
* *
*
-7.5
-10.0
-12.5
-15.0
-17.5
* *
BW change(Kg) BW change(%)
BM I(Kg/M 2)
Wu CH, et al. 2008: submitted
BF change(%)
Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).
Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
合理實際的減重目標
2000年亞太肥胖組織共識
• 目標
• 治療成功
•
•
•
•
•
•
•
•
•
•
•
•
減輕多餘體重
維持BMI
血壓
血糖
血糖控制(HbA1c)
其他危險因素
5-6Kg或初始體重的10%
< 23 kg/M 2
任何程度的下降
任何程度的下降
任何程度的改善
任何程度的減少
Cardinal Behaviors of Successful Longterm Weight Management
National Weight Control Registry Data
• Self-monitoring:
– Diet: record food intake daily, limit certain foods or food
quantity
– Weight: check body weight >1 x/wk
• Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%
• Eat breakfast daily
• Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Pathogenesis of Metabolic syndrome
2 major, interacting causes
• Obesity and abnormal body fat distribution
disorders of adipose tissue.
• Endogenous metabolic susceptibility
Insulin resistance
• A constellation of independent factors
(e.g. molecules of hepatic, vascular, and immunologic
origin) Contributors: aging , proinlfammatory state,
hormonal change.
Grundy SM et al: Circulation 2004;109:433-8
Grundy SM: Am J Clin Nutr 2006 Aug 1248
Mean Efficacy of Pharmacological
Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36
Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4): 935-82
Weight Change (kg)
Metformin- Mean Weight Change
0
Placebo
Metformin
-2
Lifestyle
-4
-6
-8
0
1
2
3
Years from Randomization
The DPP Research Group, NEJM 346:393-403, 2002
4
Weight Change of DM patients using
Acarbose in Taiwan
80
Hung YJ, et al. Clin Drug Invest 2006;26:559-65
70
60
50
kg 40
30
20
10
0
Patients
Initial visit
65.5
First follow-up
65.5
Second follow-up
65.2
Third follow-up
65.1
Similar Effect of Hypoglycemic Agents
Action on
insulin
resistance
Action on
insulin
secretion
HbA1C
reduction
Primary Goal
Glinides
0/+
+++
0.9 to 1.7%
Postprandial
Conventional
Sulfonylureas
0/+
++++
1% to 2%
Fasting
New SU
++
+++
1% to 2%
Fasting
Biguanides
++
0
1% to 2%
Fasting
Glitazones
++++
0
0.5% to 1.3%
Fasting
0
0
0.5% to 1%
Postprandial
-glucosidase
inhibitors
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573 - Gitlin, et al. Ann Intern Med. 1998;129:36-38 - Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537 - De Fronzo, et al. N Engl J Med. 1995;333:541-549 - Bailey & Turner. N Engl J Med. 1996;334:574-579
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 - Goldberg, et al. Diabetes Care 21:1897-1903
Characters of individuals in MetS of
NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
Intra-abdominal adiposity promotes insulin
resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin
FFA
Insulin resistance
Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation
Metabolic Syndrome
• Pathology:
Visceral Fat, Atherosclerosis
• Physiology:
Insulin Resistance
• Assessment: Abdominal Obesity, CAD risk
• Regimen:
Weight reduction, Insulin Sensitizer
Fat Topography in MetS and Diabetic Subjects
High TG
High FFA
Intramuscular
Fat
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
Effect of Thiazolidinediones
on Fat Topography
High TG
High FFA
Intramuscular
Fat
TZD
Subcutaneous
Fat
Intrahepatic
Fat
Intraabdominal
Fat
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..
TG
FFA
Diabetes prevention trials
Study
Intervention
ACT NOW
DREAM
Finnish DPS
Da Qing study
DPP
Pioglitazone vs placebo
Rosiglitazone vs placebo
Intensive lifestyle vs control
Intensive lifestyle vs control
Intensive lifestyle vs placebo
Metformin vs placebo
Troglitazone vs placebo
Metformin + lifestyle
Metformin
Troglitazone (after gestational diabetes)
Gliclazide or intensive lifestyle
IDPP
TRIPOD
Fasting Hyperglycemic
Study
STOP-NIDDM
XENDOS
Acarbose vs placebo
Orlistat + lifestyle vs placebo
RR (%)
78%
62%
58%
38%
58%
31%
75%
31%
19%
50%
No effect
25%
37%
ACTosNOW. Diabetologia 2008
DREAM Trial Investigators. Lancet 2006; 368:1096–1105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A,
et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002;
Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
ADOPT (A Diabetes Outcome Progression Trial)
-Fasting Plasma Glucose Over Time-
160
Rosiglitazone vs Metformin
9.8 (12.7 to 7.0), P<0.001
Rosiglitazone vs Glyburide
17.4 (20.4 to 14.5), P<0.001
150
Glyburide
mg/dl
Metformin
140
Rosiglitazone
130
120
0
0
1
2
3
Time (years)
4
5
Other Adverse Events
Rosiglitazone
(N = 1456)
Metformin
(N = 1454)
Glyburide
(N = 1441)
335 (23%)
557 (38%)
316 (22%)
100 (7%)
18 (1%)
47 (3%)
Hypoglycaemia, n (%)
142 (10%)
168 (12%)
557 (39%)
Oedema, n (%)
205 (14%)
104 (7%)
123 (9%)
Gastrointestinal, n (%)
Weight gain, n (%)
P<0.05 vs. rosiglitazone
NEJM 2007;356;437-40
Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Meglitinides
Liver
DPP-4 inhibitors
↓Glucose level
Hepatic glucose
overproduction
Biguanides
Gut
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
DPP-4 inhibitors (indirect)
α-Glucosidase inhibitors
Biguanides (indirect)
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303;
Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
Developing Avenue of Ideal OADs
OADs
Glycemic
Effect
B-cell
Preserve
Insulin
Sensitizing
Neutral
Weight
SU
+++
Non-SU
++
BG
++
A-GI
++
Glitazone
+++
++
++
-
Gliptins
++
++
+/-
+
Low
Hypoglycemia
QD
Dosage
+/-
+
+
+
++
+
++
+
++
+
Weight gain with antidiabetic therapy
UK Prospective Diabetes Study and Update
Weight change (kg)
Modified from UKPDS 34. Lancet 1998; 352: 854-65
7
Insulin
6
5
Glitazones (supposed)
Chlorpropamide
Glibenclamide
4
3
Meglitinides (?)
Diet alone
Metformin, Acarbose
DPP-4 inhibitors (?)
2
1
0
-1
0
2
4
Years from randomisation
6
8
10
Trends in the prescribing patterns of OADs for
outpatients in Taiwan, 1997-2003
Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Combination = 62.9%
Any three OAD = 10.9%
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
TG
Metabolic syndrome
BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
HDL
Monocyte/
macrophage
Cardiovascular Disease Mortality
Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16.
Cumulative hazard, %
15
Metabolic syndrome
Yes
No
RR (95% Cl), 3.55 (1.98–6.43)
10
5
0
0
2
4
6
8
Follow-up, y
10
12
Disability-adjusted life years (DALYs) attributable
to high blood pressure in 2001
Lawes CCM, et al. Lancet 2008; 371: 1513–18
M/L
F/L
F/H
Effect of antihypertensive agents in patients
with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724.
SBP after 48 months
Acebutolol
(n=126)
Amlodipine
(n=114)
DBP after 48 months
Chlorthalidone
(n=117)
Doxazosin
(n=121)
Enalapril
(n=119)
Placebo
(n=207)
0
-8.6
-10
-11.3
-15
-20
(mmHg)
(mmHg)
-5
-13.4
-13.9 -14.1
-14.6
*
*
*
*
*
*
*
*
*P<0.01 vs placebo
Neaton et al. JAMA 1993;270:713–724.
New-onset DM with antihypertensives
-143,153 subjects, network meta-analysisElliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
Conditions favouring use of some antihypertensive
drugs-ESC 2007 Guideline
Journal of Hypertension 2007, 25:1105–1187
Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with
hypertension and impaired glucose metabolism
Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 137-147
16 weeks of combined therapy
ESH-ESC 2007 Guidelines
P. 1141
Journal of Hypertension 2007;25:1105-1187
• a1-blockers… have been shown to adequately lower blood pressure and to
also have favorable metabolic effects.
• As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT
trial) was interrupted before crucial evidence could be obtained, the overall
benefits or harm of a1-blockers for antihypertensive therapy remain
unproved.
• However, all these agents have been frequently used as added drugs in
trials documenting cardiovascular protection and can thus be employed for
combination treatment.
• a1-blockers have a specific indication in the presence of benign prostatic
hypertrophy.
Multiple antihypertensive agents
are needed to achieve target BP
Trial
Target BP (mmHg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
Number of antihypertensive agents
1
2
3
4
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure;
SBP, systolic blood pressure
DOX-EM-07004
Bakris GL, et al. Am J Kidney Dis 2000;36:646-661;
Lewis EJ, et al. N Engl J Med 2001;345:851-860;
Cushman WC, et al. J Clin Hypertens 2002;4:393-404
Combination Therapy Emphasized in All Guidelines
JNC 7
•
•
Most patients with hypertension will require 2 or more antihypertensive medications to achieve
goal BP
If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy
with 2 agents, 1 of which usually should be a thiazide-type diuretic
WHO/ISH
•
•
Less than half of hypertension patients will attain target pressures with monotherapy; as many as
30% will need 3 or more drugs
Diuretic should be a component of combination therapy
ESH-ESC 2007
•
•
•
Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number
of hypertensive patients
Use of more than one agent is necessary to achieve target BP in the majority of patients.
In several patients BP control is not achieved by two drugs and a combination of three of more
drugs is required.
Chobanian et al. JAMA. 2003;289:2560-2572; WHO Writing Group. J Hypertens. 2003;21:1983-1992. ESH-ESC J.
Hypertens. 2007;25:1105-1187
Model for Origins of Atherogenic Dyslipidemia of
Obesity and MetS
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
TG
pool
Pattern A
<90
LPL
LPL
Smaller
VLDL
Large
LDL
IDL
Low
High
LDL-R
LPL
Larger
VLDL
Plasma TG
LPL/HL
Small
LDL
Remnants
HL
Smaller
LDL
Chol
>175
TG
CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL,
high-density lipoprotein; HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL
receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL,
very-low-density lipoprotein.
CETP
HDL
Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Smaller
HDL
Pattern B
HDL Cholesterol, Very Low Levels of LDL
Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:1301-10.
BNHI Treatment Guideline - Taiwan
Without CVD Patients
• ≧ 2 Risk Factors
– TC ≧ 200 mg/dL or LDL ≧ 130
mg/dL
TC < 200mg/dL
LDL < 130mg/dL
• TG ≧200 mg/dL
– TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
With CVD or DM Patients
• TC ≧200mg/dL
< 160mg/dL
• LDL ≧130mg/dL
100mg/dL
• TG ≧200 mg/dL
-
TC/HDL >5 or
HDL< 40 mg/dL
TG < 200mg/dL
Taiwan Association of Diabetes
(n=7541)
(%)
Total (n = 7541)
A+B+C
4.1 (n=310)
A1C test >1x/year
96.6 (n=7288)
A1C>9.5
14.9 (n=1121)
A1C >9
20.0 (n=1507)
A1C 7-9
11.4 (n=857)
A1C<7
31.3 (n=2363)
BP<140/90
64.9 (n=4893)
BP<130/80
30.6 (n=2305)
LDL-C<130
56.4 (n=4255)
LDL-C<100 or TC<160
33.4 (n=2516)
LDL test frequency
79.8 (n=6018)
Source: TADE 2005 data
Trends of Higher Dosage of Statins
Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
27
28
% Reduction in LDL-C
0
10
19
20
Simvastatin
20/80 mg
35
Atorvastatin
10/80 mg
37
46
12
30
31
40
50
Rosuvastatin
10/40 mg
10
37*
12
40
12
18
47
9
55
60
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
55
Statins limitation ( rule of 6% )
% Patients of AEs
LDL-Reduction (%)
10
20
80
40
-10
-20
+10 mg
+20 mg
+40 mg
mg
Statin
-30
-40
- 6%
- 6%
- 6%
-50
2,5
2,0
1,5
1,0
0,5
0
10 mg 20 mg 40 mg 80 mg
Atorvastatin
20 mg 40 mg 80 mg
Lovastatin
20 mg 40 mg 80 mg
Simvastatin
“Physicians Desk Reference (PDR)”
Lipid Lowering through Dual Inhibition
of Both Cholesterol Production and Absorption
Production in liver
Absorption from intestine
Bloodstream
LDL-C
Dietary cholesterol
Biliary cholesterol
VLDL
Cholesterol
synthesis
(HMG-CoA
Chylomicrons
reductase)
Statin
Ezetimibe
Points of
therapeutic
intervention
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001;
55:710–716.
Ezetimibe Plus Statins in Patients
with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20:1437-45.
% of patients achieving target goal of LDL-C
Statin + PL
DM
Non-DM
MetS
Non-MetS
Statin + EZE
N
% to goal
N
% to goal
80
17.5
73
83.6*
149
20.1
128
67.2*
81
27.2
78
71.8*
160
15.6
154
65.6*
* p < 0.001 vs. Statin + Placebo
•Further reduction in LDL-C ranging from 22.1-27.2% across the 4 subgroups
Relation Between CHD Events and
LDL-C in Statin Trials
30
LIPS-Pl
GREACE-UC
4S-PI
Secondary
Prevention
25
LIPS-RX
20
% With
CHD Event
4S-Rx
15
GREACE-SC
LIPID-PI
CARE-PI
LIPID-Rx
10
WOSCOPS-PI
Primary
Prevention
AFCAPS-PI
CARE-Rx
5
WOSCOPS-Rx
AFCAPS-Rx
0
90
110
130
150
170
190
210
Mean LDL-C Level at Follow-up (mg/dL)
PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care.
Athyros VG et al. Curr Med Res Opin. 2002;18:220-228. Downs JR et al. JAMA. 1998;279:1615-1622. Heart Protection
Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4S
Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:
1001-1009. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
Goals for Management of Hyperlipidemia
in Patients With Diabetes
LDL-C Goal
Guidelines
ESC/EASD 2007
ADA/AHA/ACC 2007
JBS2 2005
NCEP ATP III 2004
Diabetes With CVDa
Diabetes Without CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for
the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 =
Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
aOptional/reasonable
goals; bOr LDL-C reduction of 30% from baseline
Rydén L, et al. Eur Heart J. 2007 doi:10.1093/eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41;
Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005;
91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239.
Upcoming 2009
Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92
Acknowledgement
ORC, SLRHC, NY, USA
• Xavier Pi-Sunyer
• Dympna Gallagher
• Jack Wang
• Stanley Heshka
• ZiMian Wang
• Richard N. Pierson,Jr
• Yiying Zhang
• Experts in ORC……
Kyoto University, Japan
• Kazuwa Nakao
• Yoshihiro Ogawa
Inje University, Korea
• Jaeheon Kang
NCKU, Taiwan
• Chih-Jen Chang
• Yi-Ching Yang
• Mi-Cha Ma
• Wei-Jen Yao
• Cho-Jeng Peng
• Shu-Hui Chen
NTU, Taiwan
• Kuo-Chin Huang
• Keh-Song Tsai
CMCU, Taiwan
• Wen-Yuan Lin
WF Hospital, Taiwan
• Liu Tsan-Hung
ChangHwa Christian H, Taiwan
Shih-Te Tu
VGH Taipei, Taiwan
Low-Tone Ho
Ching-Fai Kwok
YangMing University, Taiwan
Jin-Jong Chen
Beijing Capital H, China
Xiangyan Ruan
Nat’l KS Normal Univ, Taiwan
Ray-Tai Chang
TSGH Taipei, Taiwan
Shih Kwan-Jong
Chu Nan-Fong