1. Metabolic Syndrome Symposium Dar Al-Kalima Health and Wellness Center Bethlehem, Palestine Oct. 2005

2. Metabolic Syndrome: What is it? Is it important? How common is it? What should be done about it?

3. Metabolic Syndrome Concept - Not New: 1923 - Kylin first to describe the clustering of hypertension, hyperglycemia, hyperuricemia 1936 - Himsworth first reported Insulin insensitivity in diabetics 1965 - Yalow and Berson developed insulin assay and correlated insulin levels & glucose lowering effects in resistant and non-resistant individuals

4. History (cont.) 1988 - Reaven in his Banting lecture at the ADA meeting coined the term Syndrome X and brought into focus the clustering of features of Metabolic Syndrome Reaven now prefers the name, Insulin- Resistance Syndrome - feels insulin resistance is the common denominator for Metabolic Syndrome Literature now extensive

5. Other Names Used: Syndrome X Cardiometabolic Syndrome Cardiovascular Dysmetabolic Syndrome Insulin-Resistance Syndrome Metabolic Syndrome Beer Belly Syndrome Reaven’s Syndrome etc.

6. Clustering of Components: Hypertension Hypertriglyceridemia Low HDL-cholesterol Obesity (central) Impaired Glucose Handling Microalbuninuria (WHO)

7. Is it a Syndrome? The Metabolic Syndrome: Time for a Critical Appraisal. –Joint Statement from the American Diabetes Association and the European Association for the Study of Diabetes –Kahn, R, et al. Diabetes Care 2005;28:2289- 2304

8. Is it a Syndrome? “…too much clinically important information is missing to warrant its designations as a syndrome.” “Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the ‘metabolic syndrome’.”

9. Criteria for diagnosis: World Health Organization International Diabetes Federation (IDF) - European Association for the Study of Diabetes (EASD) National Cholesterol Education Project, Adult Treatment Panel (NCEP-ATP III) Others

10. Hypertension: IDF: –BP >130/85 or on Rx for previously Dxed hypertension WHO: –BP >140/90 NCEP ATP III: –BP >130/80

11. Obesity: IDF: –Central obesity - waist circumference >94 cm for Europid men, >80 Europid women with ethnicity specific values for other groups WHO: –Waist-hip ratio >0.9 - men or >0.85 - women ATP III: –Waist circumference >40 in. - men, 35 in. - women

12. Glucose Abnormalities: IDF: –FPG >100 mg/dL (5.6 mmol.L) or previously diagnosed type 2 diabetes WHO: –Presence of diabetes, IGT, IFG, insulin resistance ATP III: –FBS >110 mg%, 100)

13. Dyslipidemia: IDF: –Triglycerides - >150mg/dL (1.7 mmol/L) – HDL - <40 mg/dL (men), <50 mg/dL (women) WHO: –Triglycerides - >150 mg/dL (1.7 mmol/L) –HDL - 39 mg/dL) women ATP III: –Same as IDF

14. Necessary Criteria to Make Diagnosis: IDF: –Require central obesity plus two of the other abnormalities WHO: –Also requires microalbuminuria - Albumen/ creatinine ratio >30 mg/gm creatinine ATP III: –Require three or more of the five criteria

15. Linked Metabolic Abnormalities: Impaired glucose handling/insulin resistance Atherogenic dyslipidemia Endothelial dysfunction Prothrombotic state Hemodynamic changes Proinflammatory state Excess ovarian testosterone production Sleep-disordered breathing

16. Resulting Clinical Conditions: Type 2 diabetes Essential hypertension Polycystic ovary syndrome (PCOS) Nonalcoholic fatty liver disease Sleep apnea Cardiovascular Disease (MI, PVD, Stroke) Cancer (Breast, Prostate, Colorectal, Liver)

17. Prevalence of Metabolic Abnormalities: Global - approx. 314 million people with impaired glucose metabolism (500 million by 2025) Palestine: (Hanan F. Abdul-Rahim, MSC) –HTN - 25.4%(R) vs 21.5% (U) –Diabetes - 9.8%(R) vs 12%(U) –IGT -8.6%(R) vs 5.9%(U) –(17% of both groups had either DM or IGT!!) –Hypertriglyceridemia - 22.6%(R) vs 34.8%(U)

18. Prevalence - Palestine: (cont.) Low HDL - 28.3%(R) vs 61.2% (U) Overall Obesity - 28.2%(R) vs 41.5%(U) Central Obesity - 65.7%(R) vs 39.0% (U) Clustering of components with and without diabetes were similar in both populations. Individuals with DM or IGT - 73.4% also had two additional components of Met. Syn.

19. Prevalence in U.S.: Varies with ethnicity: – Native Americans with diabetes - 55.2% –Metabolic syndrome more prevalent in Mexican/Americans and African Americans than non-Hispanic caucasians (ATP III) –Prevalence increasing in juveniles as well as adults due to overnutrition and sedentary life- styles, smoking Prevalence increases with aging

20. Insulin Resistance: Etiology is polygenic and environmental (overnutrition, sedentary life-style) Sensitivity to insulin varies widely in the general population Insulin-mediated glucose uptake by cells is compromised As beta cells fail and insulin is insufficient, hyperglycemia occurs

21. Insulin Resistance: Hyperinsulinemic individuals are at risk for developing diabetes, hyperlipidemia, HTN, & ultimately cardiovascular disease Patients with Metabolic Syndrome are 3.5 times as likely to die from CVD as normal people

22. Multiple Risk Factor Management Obesity Glucose Intolerance Insulin Resistance Lipid Disorders Hypertension Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease

23. Diabetes Control - How Important? For every 1% rise in Hgb A1c there is an 18% rise in risk of cardiovascular events & a 28% increase in peripheral arterial disease Evidence is accumulating to show that tight blood sugar control in both Type 1 and Type 2 diabetes reduces risk of CVD Goals: FSBS - premeal 90-130, postmeal <180. Hgb A1c <7%

24. BP Control - How Important? MRFIT and Framingham Heart Studies: –Conclusively proved the increased risk of CVD with long-term sustained hypertension –Demonstrated a 10 year risk of cardiovascular disease in treated patients vs non-treated patients to be 0.40. –40% reduction in stroke with control of HTN Precedes literature on Metabolic Syndrome Goal: <130/80

25. Lipid Control - How Important? Multiple major studies show 24 - 37% reductions in cardiovascular disease risk with use of statins and fibrates in the control of hyperlipidemia. Goals: LDL <70 mg% (<2.6 mmol/l) Triglycerides <150 mg% (<1.7 mmol/l) HDL >40 mg% (>1.1 mmol/l)

26. Medications: Hypertension: –ACE inhibitors, ARBs –Others - thiazides, calcium channel blockers, beta blockers, alpha blockers Hyperlipidemia: –Statins, Fibrates, Niacin Platelet inhibitors: –ASA, clopidogrel

27. Insulin Resistance/Diabetes: Insulin Sensitizers: –Biguanides - metformin –PPAR α, γ & δ agonists - Glitazones, Glitazars –Can be used in combination Insulin Secretagogues: –Sulfonylureas - glipizide, glyburide, glimeparide, glibenclamide –Meglitinides - repaglanide, netiglamide

28. Insulin Insulin Analogues: –Lys-pro/Aspart/glulysine used with meals –Glargine as basal insulin Continuous Subcutaneous Insulin Infusion (CSII) NPH/Regular, NPH/logs - Mixed or in fixed combinations (70/30, 75/25, 50/50) Insulin combined with oral agents

29. New Pharmacologic Agents: Incretin Mimetics: –GLP-1 agonist - exenatide Dual PPAR Dual Agonists: –Glitazars CB1 Endocannabinoid Receptor (Appetite) Antagonist: –Rimonabant

30. Antihypertensive Medications: Angiotensin-converting Enzyme Inhibitors (ACEI) Angiotensin II Receptor (ARB) Blockers Combination with Thiazides, Calcium Channel Blockers, Cardioselective Beta Blockers Target BP: <130/80

31. Life-Style Modification: Is it Important? Exercise –Improves CV fitness, weight control, sensitivity to insulin, reduces incidence of diabetes Weight loss –Improves lipids, insulin sensitivity, BP levels, reduces incidence of diabetes Goals: Brisk walking - 30 min./day 10% reduction in body wt.

32. Smoking Cessation/Avoidance: A risk factor for development in children and adults Both passive and active exposure harmful A major risk factor for: –insulin resistance and metabolic syndrome –macrovascular disease (PVD, MI, Stroke) –microvascular complications of diabetes –pulmonary disease, etc.

33. Screening/Public Health Approach Public Education Screening for at risk individuals: –Blood Sugar/Hgb A1c –Lipids –Blood pressure –Tobacco use –Body habitus –Family history