Why Metabolic Syndrome is so important
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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 isBMI.
‡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