Transcript Why Metabolic Syndrome is so important

The Evolution of
Metabolic Syndrome:
A Staged Approach to Reducing
Macrovascular and Diabetes Risks
Chaicharn Deerochanawong M.D.
Diabetes and Endocrinology unit,
Department of Medicine,
Rajavithi Hospital,
Ministry of Public Health
Topic
• Evolution of metabolic syndrome
• New definition
• Current concept of the causes of
metabolic syndrome: Adiponectin
• Goals and guidelines of treatment
• Role of statin in prevent atherosclerosis
and diabetes in metabolic syndrome
Evolution of metabolic syndrome
• 1988
Syndrome X ( Reaven )
• 1989
Deadly quartet
• 1992
Insulin resistance syndrome ( Defronzo )
• 1994
Metabolic syndrome ( Alberti )
• 1998
WHO : Metabolic syndrome
( Kaplan )
WHO definition of ‘Metabolic Syndrome’
AT LEAST ONE OF:
• IGT
• type 2 diabetes
• insulin resistance*
* Insulin resistance defined under
hyperinsulinemic, euglycemic
conditions as glucose uptake below
the lowest quartile for the background
population under investigation
+
AT LEAST TWO OF:
• impaired glucose regulation or diabetes
• insulin resistance*
•  arterial pressure
 140/90 mmHg
•  plasma triglycerides
 150 mg/dl and/or
 HDL cholesterol
< 35 mg/dl for men;
< 39 mg/dl for women
• central obesity
waist:hip ratio > 0.90 for men, > 0.85 for
women; and/or BMI > 30 kg/m2
• microalbuminuria
urinary albumin excretion rate  20 g/min
or albumin to creatinine ratio  30 mg/g
World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications.
Part I: Diagnosis and classification of diabetes mellitus. WHO Department of Noncommunicable Disease Surveillance; 1999.
Evolution of metabolic syndrome
• 1988
Syndrome X ( Reaven )
• 1989
Deadly quartet
• 1992
Insulin resistance syndrome ( Defronzo )
• 1994
Metabolic syndrome ( Alberti )
• 1998
WHO : Metabolic syndrome
• 2001
NCEP III : Metabolic syndrome
( Kaplan )
ATP III: The Metabolic Syndrome*
Risk Factor
Abdominal obesity†
(Waist circumference‡)
Men
Women
TG
HDL-C
Men
Women
Blood pressure
Fasting glucose
Defining Level
>102 cm (>40 in)
>88 cm (>35 in)
150 mg/dL
<40 mg/dL
<50 mg/dL
130/85 mm Hg
110 mg/dL
*Diagnosis is established when 3 of these risk factors are present.
†Abdominal obesity is more highly correlated with metabolic risk factors than isBMI.
‡Some men develop metabolic risk factors when circumference is only marginally increased.
JAMA. 2001;285:2486-2497.
Evolution of metabolic syndrome
• 1988
Syndrome X ( Reaven )
• 1989
Deadly quartet
• 1992
Insulin resistance syndrome ( Defronzo )
• 1994
Metabolic syndrome ( Alberti )
• 1998
WHO : Metabolic syndrome
• 2001
NCEP III : Metabolic syndrome
( Kaplan )
• ICD-9 Code “Dysmetabolic syndrome” –277.7
• 2005
IDF/ADA : Metabolic syndrome
IDF/AHA 2005:
Metabolic Syndrome
• To Identify individual at high risk of
CVD and diabetes
• To be useful for clinician
• To be useful for international
comparison
IDF/AHA 2005:
Metabolic Syndrome
• Abdominal obesity ( waist circumference by
ethnic/country specific) plus at least 2 of the
followings
1. Triglyceride > 150 mg/dl
2. HDL-C <40 mg/dl (men), <50 mg/dl (women)
3. SBP > 130 mm/Hg and/or DBP > 85 mm/Hg
4. FPG > 100 mg/dl or known diabetes
Ethnic specific values for waist circumference
Country/Ethnic group
Waist circumference
Europids
Male
> 94 cm
In the USA, the ATP III values (102 cm
male; 88 cm female) are likely to continue to
be used for clinical purposes
Female
> 80 cm
South Asians
Male
> 90 cm
Based on a Chinese, Malay and AsianIndian population
Female
> 80 cm
Chinese
Male
> 90 cm
Female
> 80 cm
Male
> 85 cm
Female
> 90 cm
Japanese
Ethnic South and Central
Americans
Use South Asian recommendations until
more specific data are available
Sub-Saharan Africans
Use European data until more specific data
are available
Eastern Mediterranean and Middle
East (Arab) populations
Use European data until more specific data
are available
Obesity
• Android obesity ( apple shape )
predominate visceral fat
• Gynoid obesity ( pear shape )
predominate subcutaneous fat
Visceral
Obesity
Subcutaneous
Obesity
18
16
P < 0.0001
14
12
10
8
6
4
2
0
0
1,000
2,000
3,000
4,000
Visceral adipose tissue volume
per unit surface area (ml/m2)
5,000
Glucose disposal (mg/kg LBM/min)
Glucose disposal (mg/kg LBM/min)
Visceral obesity is associated
with insulin resistance
Women
Men
18
16
14
12
10
8
6
4
2
0 0
5,000
10,000
15,000
20,000
Total subcutaneous adipose tissue volume
per unit surface area (ml/m2)
Banerji MA, et al. Am J Physiol 1997; 273:E425–E432.
Waist circumference is a surrogate
marker of visceral fat
Men
> 40 inch
> 36 inch or
90 cm( Asia )
Women
inch
> 35 inch
> 32 inch or
80 cm( Asia )
Epidemiology of
Metabolic Syndrome
Metabolic syndrome
Prevalence of components
*US adults age 20 and over (NHANES III,1988-94)
• Abdominal obesity
39%
• Hypertriglyceridemia
30%
• Low HDL cholesterol
37%
• High blood pressure or medication use 34%
• High fasting glucose or medication use 13%
• >1
• >2
• >3
71%
44%
24% (~45% of people age 50-70 years)
Ford et al. JAMA;287:356-9,2002
Metabolic Syndrome
in Thailand
Chaicharn Deerochananwong M.D.
For the Endocrine Society of Thailand
Prevalence of Metabolic Syndrome
• Prevalence of Metabolic Syndrome by
NCEP ATPIII in Thai High Risk
Population = 24.1 % ( Male 22.2% and
female 24.7% )
• If using waist circumference cut off
point by WHO Asian Guideline ( Male >
90 cm, Women > 80 cm ), the
prevalence of metabolic syndrome in
Thai High Risk Population= 33.3 %
( Male 36.0% and female 32.6% )
Prevalence of Metabolic Syndrome
( NCEP ATPIII ) by Risk Factors
•
•
•
•
•
Obesity
Hypertension
Dyslipidemia
GDM or macrosomic baby
FH of diabetes
38.2%
34.2%
29.4%
17.9%
14.1%
Prevalence of Metabolic Syndrome
( NCEP ATPIII )by Age
70
60
50
40
Male
30
Female
Total
20
10
0
20-29 yr
30-39 yr
40-49 yr
50-59 yr
60-69 yr
>70 yr
Metabolic Syndrome and Mortality
• Population based, prospective 1209 Finnish
men aged 42-60 year at baseline (1984-9),
follow-up through December 1998
• Relative risk
NCEP III
CHD Mortality
2.9 (1.2-7.2)
CVD Mortality
2.6 (1.4-5.1)
All cause Mortality1.9 (1.2-3.0)
WHO
4.2 (1.6-10.8)
3.0 (1.5-5.7)
2.1 (1.3-3.3)
Lakka. JAMA 2002;288:2709-16
Metabolic syndrome: The Role of Obesity
Visceral Obesity
FFA,
cytokines, adipokines
 Triglycerides
 HDL
 Insulin
Resistance
 Blood glucose
 Type 2 Diabetes
Cardiovascular
Disease
Blood Pressure
Causes of Metabolic Syndrome
• Genetic causes
• Acquired causes
Overweight and obesity
Physical inactivity
Genetic causes of
Metabolic Syndrome
•
•
•
•
•
Beta3-adrenergic-receptor gene
Cd36, Fatty acid transporter (FAT) gene
11 beta-HSD1 gene
Adiponectin gene
Etc.
TNF-
IL-6, IL-8
MCP-1
TGF 
IGF-1
FGF
Bone Morphogenic Protein IGFBP
Fatty acids
EGF
Lysophospholipid
Visfatin
Lactate
Adenosine
Resistin
Adipose Tissue
Prostaglandins
Glutamine
Adiponectin
Unknown Factors
Adipsin
Agouti
Estrogen
Angiotensin-II
Angiotensin
Leptin
Retinol
Plasminogen activator
inhibitor -1
Acylation-Stimulating Protein
Adiponectin
1 18
41
107
Collagenlike
Fibrous
Domain
244
C1q-like
Globular
Domain
Adiponectin:
A ‘Good’ Fat-Derived Hormone
• Secreted by adipocytes (SC)
• Abundant in blood (ug/ml)
• Reduced in obesity / T2DM / CVD
• Specific receptors (2) in many tissues
• turns on fat oxidation
• Improves insulin sensitivity
Lancet, 1 Nov 2003
LOW Plasma Adiponectin Is
Correlated With Insulin Resistance
Weyer, et al., JCEM, 86, No. 5, 2001
Adiponectin:
A ‘Good’ Fat-Derived Hormone
• Increases fatty acid oxidation
• Improves insulin action in liver
and skeletal muscle
• Anti-atherogenic / anti-inflammatory
Adiponectin and Atherogenesis
Matsuda, et al JBC 277 (40) 37487-37491, 2002
Hypoadiponectinemia and CAD
＊
Plasma Adiponectin (g/ml)
20
p<0.01
15
10
5
0
non-CAD
CAD
Circulation 199
6 year risk of myocardial infarction
adjusted relative risk (p< 0.001)
lipid adjusted RR (p < 0.02)
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1
(7.9)
2
(12.6)
3
(16.5)
4
(21.1)
5
(29.2)
g/ml
quintile of adiponectin
Pischon, T., et al., JAMA, 2004. 291(14): p. 1730-7.
Adiponectin
• Unique adipocyte-derived hormone
with
antidiabetic effect
antiinflammatory effect
antiatherogenic effect
Goal of Treatment
of Metabolic Syndrome
• Prevent atherosclerosis events
• Prevent type 2 diabetes
Objectives of Management
• To reduce underlying causes
Obesity and physical inacitivity
• To treat associated risk factors
High blood pressure
High blood sugar
Dyslipidemia
Prothrombotic state
Modest weight loss has
beneficial health effects
Modest weight loss of >5% in obese
individuals with type 2 diabetes, hypertension
or hyperlipidaemia resulted in:
•
•
•
•
Improved glycaemic control
Reduced blood pressure
Improved lipid profile
20% reduction in premature mortality in
overweight women with obesity-related
health conditions
Goldstein DJ. Int J Obesity 1991; 16: 397–415
Clinical Management of
Metabolic Syndrome
•
Therapeutic Lifestyle Changes
- Dietary restriction of calories, simple
carbohydrates, and saturated fat
- Regular aerobic exercise
•
Pharmacologic therapy
Clinical Management of
Metabolic Syndrome
•
•
Therapeutic Lifestyle Change
Pharmacologic therapy
-Insulin sensitizing drugs
-Weight loss drugs
-Drugs for heart disease prevention
eg. ACEI, aspirin, statin
Studies in The Prevention of Type 2 DM
Baseline Patient Characteristics
Age
BMI
OGTT (% pts)
IGT
Normal
DPS1
55
31
100
0
DPP2
51
34
100
0
STOP-NIDDM3
55
31
100
0
XENDOS4
43
37
21
79
1. Tuomilehto J et al. N Engl J Med 2001; 344: 1343-50
2. DPP N Engl J Med. 2002; 346: 393-403
3. Chiasson J-L et al. Lancet 2002; 359: 2072-77
4. Sjostrom et al. 9th ICO, Sao Paulo 2002. Poster Presentation
Diabetes Prevention Study
( NEJM 2001;344:1343-50 )
• Mean duration of follow-up was 3.2 years
• The intervention group: mean weight loss at the
end of year 1 and 2 = 4.2 kg and 3.5 kg
respectively compared with 0.8 kg in both year
in control group
• The cumulative incidence of diabetes after four
years was 11% in the intervention group and
23% in the control group
• During the trial, the risk of diabetes was reduced
by 58% ( P<0.001) in the intervention group
• The reduction in the incidence of diabetes was
directly associated with changes in lifestlye
Diabetes Prevention Program
( NEJM 2002;346:393-403)
40
Cumulative incidence
of diabetes (%)
Placebo
RR*
31%
30
Metformin
RR*
58%
Lifestyle
20
10
0
0
0.5
1.0
1.5
2.0 2.5
Year
*Reduction in risk of progressing to type 2 diabetes versus placebo
3.0
3.5
4.0
DPP.N Engl J Med. 2002; 346: 393-403
Diabetes Prevention Program
CVD Risk factors
BMI
Systolic BP
Diastolic BP
Triglyceride
Total cholesterol
LDL-C
HDL-C
CRP
Fibrinogen
Placebo
-0.4%
-0.6+0.5
-1.9+0.3
-11.2+2.7
-4.6+1.0
-2.0+0.9
-0.3+0.3
0%
+2.4%
Met
-2.9%*
-0.3+0.5
-1.6+0.3
-8.2+2.8
-4.1+1.1
-3.3+1.0
+0.5+0.3
-13.2%*
+1.9%
TLC
-7.2%*
-3.3+0.5*
-3.8+0.3*
-25.3+2.7*
-6.9+1.1
-2.8+0.9
+1.0+0.3*
-29.5%*
- 1.0%*
* P-value < 0.05 compare with placebo
Is Intensive Lifestyle Changes or
Metformin Cost Effective in Prevent DM?
Lifestyle
Metformin Placebo
Lifetime costs
$ 59,917
$ 64,871
Lifetime QALY
△ Cost vs Plac
△ QALY vs Plac
△ Cost /△ QALY
10.8
10.3
- $ 3,523
+ $ 1,431
0.8
0.3
Cost saving $ 5,628
$ 63,440
10.0
-
Conclusions: lifestyle intervention is cost-saving
and metformin is cost effective ( < $ 6,000 per QALY )
The Stop NIDDM Trial
Eligible criteria: age 40-70 yr, BMI 25-40, FPG > 5.6 mmol/l
Acarbose 100mg tid vs Placebo tid for 3 year and then follow up with
Placebo in 2 group for 3 months
• Results
1. Absolute risk reduction of diabetes = 9 %
2. Relative risk reduction of diabetes = 21.5%
3. A hazard ratio 0.76 (CI 0.64-0.90) to onset of DM
4. NNT to prevent 1 case in 3 years of DM = 11
5. Cumulative incidence of DM
Acarbose Placebo
At the end of treatment
32.8%
41.8%
3 Months after stop treatment
39.7%
44.9%
XENDOS Results
Effect of Orlistat on Body Weight
Change in
weight (kg)
Placebo + lifestyle
Orlistat + lifestyle
0
-3
-4.1 kg
-6
-6.9 kg
-9
p<0.001 vs placebo
-12
0
52
104
156
Week
Sjostrom et al. 9th ICO, Sao Paulo 2002. Poster Presentation
208
XENDOS Results
Cumulative Incidence of Type 2 DM
Incidence
Placebo + lifestyle
of T2D (%)
Orlistat+ lifestyle
10
9.0%
RR^
37%
8
p=0.0032
6.2%
6
4
^Hazard ratio
reduction vs placebo
plus lifestyle
2
0
0
26
52
78
104
130
156
182
Week
Sjostrom et al. 9th ICO, Sao Paulo 2002. Poster Presentation
208
Treatment of Elevated Blood Pressure
• Goal of blood pressure < 140/90 mmHg,
except for diabetes ( < 130/80 mmHg )
• No randomized controlled trial of
antihypertensive agents in patients with
metabolic syndrome and no definite
guidelines existed
• Suggestion can be made based on
assumed pathophysiologic mechanisms
ACE-I and ARB
•
May be considered preferred agents
because of
1.Metabolically neutral
2.Can prevent or retard type 2 diabetes
3.Most effective agents in preventing
proteinuria and retard the progression of
obesity hypertension-related ESRD
4.May prevent cardiac hypertrophy and
progression to heart failure
Management of Dyslipidemia
in Metabolic Syndrome
• Primary goal
LDL-Cholesterol
• Secondary goal
Hypertriglyceridemia
> 400 mg/dl: TG lowering drug
200-400
: Non-HDL-chol
Low HDL-C ( < 40 mg/dl )
LDL-C Goal and Cutpoints for Treatment
NCEP ATP III ( Circulation July13, 2004 )
Risk Category
CHD and CHD
Risk equivalents
LDL goal and
initiate TLC
<100, >100
LDL consider
drug Rx
> 100
( optional goal < 70 )
( <100 drug optional )
2+ risk factors
<130, >130
>130,160
0-1 risk factor
<160, >160
>190
Drugs for non-HDL cholesterol lowering
• 2 approaches to drug therapy
• First, the non-HDL cholesterol goal can
be achieved by LDL-lowering drug
• Second, fibrate or nicotinic acid
• Fibrate or nicotinic acid can be added
with statin, if used with appropriate
caution, to achieve the non-HDL
cholesterol goal
Lowering LDL-C With Statin Therapy
Reduces the Risk of CV Events
Many major trials have established beyond question that
LDL-C–lowering therapy reduces risk for CHD events
4S-P
Patients with CHD event (%)
25
Secondary prevention
Primary prevention
20
Pravastatin
15
CARE-P
HPS-P
PROSPER-S
10
5
Simvastatin
LIPID-P
4S-S
LIPID-S
CARE-S
HPS-S
ASCOT-S*
Lovastatin
PROSPER-P
WOSCOPS-P
Atorvastatin
WOSCOPS-S
S = statin-treated
P = placebo-treated
ASCOT-P*
AFCAPS-P
AFCAPS-S
0
*Extrapolated to 5 y
2.3
(90)
2.8
(110)
3.4
(130)
3.9
(150)
4.4
(170)
4.9
(190)
5.4
(210)
LDL-C mmol/L (mg/dL)
Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21.
PPP (WOS, CARE, and LIPID) diabetics
Diabetes
Non diabetes
(n=1,444)
(n=18,324)
Relative Risk Reduction
0
-10
-20
23%
-30
26%
(p<0.001)
(p=0.002)
(%)
* CHD Death, Non fatal MI, CABG, or PTCA: 3,717 events
Sacks F et al.: Circulation 2000; 102: 1893-1900
33490-01-N
THE METABOLIC
SYNDROME IN WOSCOPS
THE METABOLIC
SYNDROME IN WOSCOPS
YES
NO
632 (9.8%)
5815
Tg > 1.69mM
3153 (48.9%)
3294
HDL < 1.04mM
2447 (38.0%)
4000
Metabolic Syndrome
BMI > 30
Fasting PG > 6.1mM
SBP >130 / DBP >85
or on Rx
N with 3 or more RF’s
95 (1.5%)
4743 (73.6%)
1537 (23.8%)
Excluding diabetics and fasting glucose > 7.0mM.
6352
1704
4910
Pravastatin Reduces CHD In
Metabolic Syndrome (WOSCOPS)
Non Metabolic
Syndrome
Metabolic
Syndrome
（n=4,756）
（n=1,691）
CHD Prevalence
(％)
10
-27％
8
6
4
2
0
-31％
10.4%
6.2%
7.7%
4.4%
Placebo Pravastatin Placebo
Pravastatin
Circulation, 2003
Statin and Development of
Diabetes
Shimomura, Jpn. Endo. Soc. 2004
Shimomura, Jpn. Endo. Soc. 2004
Pravastatin Increases
Plasma Adiponectin Levels
WOSCOP Subanalysis
% Changes
（v.s baseline ）
40
30
p < 0.001
20
10
0
p = N.S.
-10
Placebo
Pravastatin
Shimomura, Jpn. Endo. Soc. 2004
Pravastatin might prevent
postprandial hyperglycemia
and hyperlipidaemia leading
to endothelial dysfunction
Importance of 1st phase insulin secretion
1st phase insulin secretion ↓
Postprandial
hyperglycemia
Postprandial
hyperlipidaemia
Endothelial dysfunction
Atherosclerosis progression
Yutaka Mori
Implications
• Statin that don’t affect insulin spike are
favorable for hypercholesterolemic patients
with insulin resistance.
• Some data show that hydrophobic statins like
Atorvastatin and Simvastatin inhibit insulin
secretion. On the other hand, Pravastatin
has a low lipid solubility and it doesn’t
transfer into pancreatic beta-cells and
doesn’t inhibit insulin secretion
Metabolic Syndrome
• Closely linked to insulin resistance that
caused by genetic and abdominal obesity
and physical inactivity
• First line therapies are weight reduction
and increased physical activity
• Beyond the underlying causes, to treat the
associated risk factors of atherosclerosis
are also very important