Metabolic Syndrome

Syndrome X Insulin Resistance Syndrome Dysmetabolic Syndrome Multiple Metabolic Syndrome

Components of Metabolic Syndrome

ATP III identified 6 components of the metabolic syndrome : Abdominal obesity (increased waist circumference) Insulin resistance (glucose intolerance) Atherogenic dyslipidemia (raised TGs, low HDL, increased remnant lipoproteins, elevated apolipo B, small LDL particles, and small HDL particles) Raised blood pressure Proinflammatory state (elevations of CRP) Prothrombotic state (increased plasma PAI-1 and fibrinogen)

Evolution of Metabolic Syndrome

1923: Kylin describes clustering of hypertension,
gout, and hyperglycemia

1988: Reaven describes Syndrome X

HTN, hyperglycemia, glucose intolerance, elevated TGs, and low HDL

1998: WHO defines metabolic syndrome 2001: NCEP defines metabolic syndrome and gives
ICD code

Diagnostic Criteria
WHO (1999) NCEP ATPIII (2002)

AACE Criteria 2003 2005

IDF Consensus
Central obesity: For Asian populations, 90 cm in men and 80 cm in women Plus any two of the following :

raised TG level: 150 mg % or specific t/t for this lipid abnormality reduced HDL-C: <40 mg% in males and <50 mg% in females or specific t/t for this lipid abnormality raised BP: 130/85 mmHg or t/t of previously diagnosed HTN raised fasting plasma glucose (FPG) 100 mg% or previously diagnosed type 2 DM

Significance of Metabolic Syndrome

Independent risk factor for cardiovascular
disease

In Framingham, the metabolic syndrome Predicts future Diabetes

alone predicted 25% of all new-onset CVD

CVD Mortality Increased in the Metabolic Syndrome: Kuopio Ischaemic Heart Disease Risk Factor Study
Cumulative Hazard, %
15

Cardiovascular Disease Mortality RR (95% CI), 3.55 (1.986.43)

10

Metabolic Syndrome:
YES

5 0

NO

4 6 8 Follow-up, y

1 0

1 2

Lakka HM et al. JAMA 2002;288:2709

RR - 2.96 CHD, 2.63 MI, 2.27 Stroke, 1.81 Death

Prevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+
25% 20% 15% 10% 5% 0%
% of Population =

19.2% 13.9% 8.7% 7.5%

CHD Prevalence

No MS/No DM 54.2%

MS/No DM 28.7%

DM/No MS 2.3%

DM/MS 14.8%

Alexander CM et al. Diabetes 2003;52:1210-1214..

CHD Mortality Increases with Increased Impaired Glucose Tolerance: PARIS

CHD mortality rate/1000
5

p<0.001

n=6055
0

n=690 IGT

n=158

n=135

G<140 mg/dL

G 200 mg/dL Known diabetes Newly diagnosed diabetes G - glucose

Eschwege E et al. Horm Metab Res 1995;17(Suppl):4146.

Different Components of the Metabolic Syndrome Predict Diabetes: San Antonio Heart Study Risk of Type 2 Diabetes per Unit Change in Risk Trait
Levels

FPG per mg/dl SBP per mm Hg HDL-C per mg/dl decrease BMI per kg/m2 2% 4%

8%

7%

0%

2%

4%

6%

8%

10%

Stern MP et al. Ann Intern Med 2002;136:575-581.

Prevalence : Indian Scenario

Prevalence of insulin resistance in Asian Indians ~ 550% Important and consistent observations - excess body fat and
abdominal obesity

Tremendous heterogeneity of prevalence in terms of geographical location

and adaptation of lifestyle, in addition to age, gender, and socio-economic strata.

Chennai Urban Population Study:

prevalence of CAD and hypertriglyceridaemia were higher in the middle income group (NS) The relative odds ratio for diabetes and impaired glucose tolerance increased significantly with increase in income while hypercholesterolaemia, hypertension and CAD showed no significant changes. Analysis revealed that higher social class had a strong association with the components of the metabolic syndrome

Prevalence of the NCEP Metabolic Syndrome: NHANES III by Age

50%
Prevalence, %
Men Women
23% 44%44%

40% 30% 24% 20% 10% 0%

8%

6%

2070+ 2029 3039 4049 5059 6069 20 30 60

70

Age, years
Ford ES et al. JAMA 2002;287:356-359.

Additional associated abnormalities

Coagulation abnormalities Plasminogen-activator inhibitor-1 & Fibrinogen Hyperurecemia Mircoalbuminuria Polycystic ovary syndrome Non-alcoholic steattohepatitis (NASH) Elevated total apoB Increased levels of proinsulin

Hyperleptinemia Sympathomimetic activity Sodium retention High intra-myocellular lipids Sub-clinical inflammation (CRP) Low levels of serum adiponectin Lipodystrophies Sleep Apnea

Endothelial dysfunction

Metabolic Syndrome
Prothrombotic state (fibrinogen, Factor VIIa, fibrinolytic activity)

Insulin Resistance

Hyperinsulinaemia

Hyperuricemia

Central obesity

Impaired Glucose Tolerance

Type 2 Diabetes
Diabetes Care 1998;21(2):310314. Williams G, Pickup JC. Handbook of Diabetes. 2nd Edition, Blackwell Science. 1999.

Hypertension Microalbuminuria

HDL cholesterol

Triglycerides

Small dense LDL

Dysfunctional Fat Cell

Excess production of:

Free fatty acids Interleukin-6 PAI (plasminogen activator inhibitor) Leptin Tumor necrosis factor Resistin Angiotensinogen cytokines (tumor necrosis factor) adiponectin

Central Obesity

Forget about weight, Think about shape!

Patterns of Body Fat Distribution

The Asian Indian obesity phenotype

Higher body fat with relatively less body BMI Less lean body mass High BF/BMI ratio High waisthip ratio Variable subscapular/triceps ratio High intramyocellular lipids

Data indicate that intra-abdominal fat is more in Asian Indians as

compared to other ethnic groups

Increased body fat and decreased lean body mass compensate

each other not allowing appreciable increase in the value of BMI, therefore BMI does not reflect adiposity accurately in Asian Indians.

Asian Indians at different locations

BMI WHR

The Ashwell Shape Chart to assess Syndrome X - based on waist circumference and height

Recommendations for Clinical Management of Obesity

Reduce body weight by 7% to 10% during first year of therapy. Will require decreasing caloric intake by 500 to 1000 calories/d. Continue weight loss thereafter with goal to achieve BMI 25 kg/m2 Consistently encourage weight maintenance/reduction through
appropriate balance of physical activity and caloric intake

Managing Physical inactivity

Regular moderate-intensity physical activity; at least 30 min of continuous
or intermittent (and preferably 60 min) 5 d/wk, but preferably daily

In patients with established CVD, assess risk with detailed physical activity
history and/or an exercise test, to guide prescription.

Encourage resistance training 2 d/wk. Advise medically supervised programs for high-risk patients (eg, recent ACS
or revascularization, CHF).

Multiple short (10- to 15-minute) bouts of activity (walking breaks at work,

gardening, or household work), using simple exercise equipment (eg, treadmills)

Avoiding common sedentary activities in leisure time (television watching

and computer games) is also advised

Effective Dietary Interventions for Dyslipidemia

Recommendations:
saturated fat 7% of total calories

Reduce trans fat Use monounsaturated or polyunsaturated oils

dietary cholesterol 200 mg/dL total fat 25% to 35% of total calories

simple sugars should be limited. Increase whole grains Increase fruits and vegetables Eat fish 1-2 times per week

Fatty Acids in Oils & Fats

Oil
Canola

Saturated Poly Mono

6% 32% 62%

Fat
Margarine Cottonseed Shortening Chicken fat

Saturated Poly
19% 27% 28% 31% 41% 52% 66% 32% 54% 28% 22% 12% 4% 4%

Mono
49% 19% 44% 47% 47% 44% 30%

Safflower

10%

77%

13%

Sunflower

11%

69%

20%

Corn Olive Soybean

13% 14% 15%

62% 9% 61%

25% 77% 24% Lard Beef fat Butter

Peanut

19%

33%

49%

ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy

 Insulin resistance
Metformin & Thiazolidinediones

Hypertension
No class of antihypertensive drugs has been identified as being uniquely efficacious in patients with metabolic syndrome.

Prothrombotic State
AHA currently recommends use of aspirin prophylaxis in metabolic syndrome when their 10year risk for CHD is10%.

Proinflammatory State
AHA and CDC guidelines for measurement of CRP in clinical practice suggest that measurements should be limited to individuals assessed to be at intermediate risk (10-year risk for CHD 10% - 20%). No specific therapies beyond lifestyle therapies

 Abnormal body fat distribution General body fat distribution (dual-energy

x-ray absorptiometry [DXA]) Central fat distribution (CT/MRI) Adipose tissue biomarkers:leptin,adiponectin Liver fat content (MR spectroscopy) Myocellular fat (MR spectroscopy)

Additional Measures in Need of More Research

Insulin resistance (other than elevated

fasting glucose) Fasting insulin/proinsulin levels Homeostasis model assessment for insulin resistance (HOMA-IR) Insulin resistance by Bergman Minimal Model Elevated free fatty acids (fasting and during OGTT)

Atherogenic dyslipidemia (beyond

elevated TG and non-HDL-C and low HDL) Apolipoprotein B Small LDL particles Triglycerides/HDL-C ratios

Proinflammatory state Elevated hs-CRP Elevated inflammatory cytokines (IL-6) Low levels of adiponectin

Dysglycemia Fasting glucose OGTT Vascular dysregulation (beyond

elevated BP) Measurement of endothelial dysfunction Microalbuminura Chronic renal disease

Prothrombotic state Fibrinolytic factors (PAI-1) Clotting factors (fibrinogen) Hormonal factors Corticosteroid axis Polycystic ovary syndrome

Unresolved Issues: Future Research Challenges

Improved strategies for successful weight reduction and maintenance and increased
physical activity

A better understanding of the genetic and metabolic contributions leading to the

development of the syndrome

The value of treating atherogenic dyslipidemia beyond LDL-lowering therapy The efficacy of treating insulin resistance for reducing the risk of CVD A better understanding of the relationship between a proinflammatory state and the
metabolic syndrome and the efficacy of intervention on this state for the prevention of both CVD and diabetes

Establishment of benefit and cost-effectiveness of specified goals for drug therapies

directed toward the metabolic syndrome as a whole or particular risk components

Conclusions

The metabolic syndrome is a term for a constellation of risk factors that increase the risk of developing both ASCVD and type 2 DM The syndrome is strongly associated with the presence of abdominal obesity. Weight reducton, lowering the levels of LDL-C, and blood pressure management are primary targets for risk reduction

Lifestyle interventions are the initial therapies recommended. If not sufficient, then drug therapies for individual risk factors Considerable additional research is needed to better refine the most appropriate therapies for individuals with the metabolic syndrome.

Lets hope this is not the shape of things to come?