1. Dr.Sarma@works The Core Knowledge on Metabolic Syndrome Dr.Sarma, R.V.S.N., M.D., M.Sc., (Canada) Consultant Physician and Chest Specialist, Thiruvallur, Chennai

2. Dr.Sarma@works Metabolic Syndrome The Hidden Volcano

3. Dr.Sarma@works 14.2 17.5 23% 15.6 22.5 44% 26.5 32.9 24% 1.0 1.3 33% 9.4 14.1 50% World 2000=151 million 2010=221 million Increase: 46% 84.5 132.3 57% Zimmet P et al. Nature. 2001;414:782. Global Projections for Diabetes 1995-2010

4. Dr.Sarma@works World Congress 1.First World Congress on Insulin Resistance syndrome – Nov 2003 2.Second World Congress on IRS – 2004 www.insulinresistance.us

5. Dr.Sarma@works Synonyms of Metabolic syndrome 1. Insulin resistance syndrome (IRS) 2. (Metabolic) Syndrome X 3. Dysmetabolic syndrome 4. Multiple metabolic syndrome 5. ICD code # 277.7

6. Dr.Sarma@works What is this Syndrome ? Insulin resistance – Hyperinsulinemia Hyperglycemia – IFG, IGT, DMII Pro-inflammatory state ( ￪ CRP) Pro-coagulant changes ( ￪ PAI-1, ￪ Fibrinogen) Dyslipidemia ( ￪ TG, ↓ HDL) Premature atherosclerosis, IHD, CAD Type 2 diabetes Hypertension, ED

7. Dr.Sarma@works Definitions of the Metabolic Syndrome According to clinical outcomes According to underlying causes According to metabolic components According to clinical criteria

8. Dr.Sarma@works Definition of Metabolic Syndrome: According to Underlying Causes Insulin resistance (1999 WHO) Insulin resistance syndrome Lifestyle: especially obesity (NCEP ATP III) Metabolic syndrome Sub-clinical inflammation WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

9. Dr.Sarma@works Causes Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (>60% of energy intake) in some persons Genetic causes Metabolic Syndrome Currently, 47 million U.S. adults- metabolic syndrome. Leading health problem in U.S.

10. Dr.Sarma@works Secondary Pregnancy Stress Infection Uremia Glucocorticoid excess Acromegaly Metabolic Syndrome

11. Dr.Sarma@works The Worsening Epidemic of Obesity and Diabetes 1999-2000 NHANES Data (JAMA, Oct 2002) 31% obese (BMI 30), increase from 23% 65% overweight (BMI 25), increase from 56% 4.7% extremely obese (BMI 40), ￪ from 2.9% No physical activity in 27%! No regular activity in additional 28% Each 1-kg increase in weight = remember 9% increase in risk of diabetes How can lifestyle changes be implemented long term? NHANES=National Health and Nutrition Examination Survey.

12. Dr.Sarma@works How It works ?

13. Dr.Sarma@works Plausible Mechanisms Mixed IR – CHO IR, FFA no IR Lipotoxic state - ￪ FFA TNF–alpha, IL -6 – Adipocytokine - ￪ FFA PPAR–gamma – nuclear enzyme ￪ ↓ Adiponectin – ↓FFA oxidation, ￪ FFA – IR FFA – IR – JNK mediated Satiation signaling – Leptin Resistance

14. Dr.Sarma@works Insulin Resistance: Receptor and Postreceptor Defects Peripheral tissues (skeletal muscle) Increased glucose Pancreas Liver Impaired insulin secretion Increased glucose production X Insufficient glucose disposal Causes of Hyperglycemia in Type 2 Diabetes

15. Dr.Sarma@works Metabolic Syndrome, Insulin Resistance, and Atherosclerosis MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718. Hyperinsulinemia/hyperproinsulinemia Glucose intolerance Increased triglycerides Decreased HDL cholesterol Increased BP Endothelial dysfunction Small, dense LDL Atherosclerotic cardiovascular disease Increased PAI-1 Insulin resistance

16. Dr.Sarma@works Normal Type 2 Diabetes Courtesy of Wilfred Y. Fujimoto, MD. Visceral Fat Distribution: Normal vs Type 2 Diabetes

17. Dr.Sarma@works Thiazolidinediones Adipose tissue MuscleLiver Decreased FFA and TNF  release Decreased tissue triglycerides Increased adiponectin Decreased glucose output Increased glucose utilization  -cell Increased insulin secretion Vascular Increased endothelial function PPAR  Adapted from Goldstein BJ. Am J Cardiol. Suppl 2002. Effects of Thiazolidinediones Mediated via Adipose Tissue

18. Dr.Sarma@works NO reduction Vascular constrict. NO reduction Vascular constrict. NO production Vascular dilation NO production Vascular dilation Adapted from Steinberg H et al. Diabetes. 2000;49:1231. Thiazolidinediones Insulin Resistance Shear stress Increased visceral fat Increased lipolysis Increased FFA levels - Endothelium Increased TNF  - Decreased adiponectin - FFA and Adipokines in Endothelial Dysfunction -

19. Dr.Sarma@works Multiple Factors May Drive Progressive Decline of  -Cell Function Adapted from Unger RH, Orci L. Biochim Biophys Acta. 2002;1585:202-212. Hyperglycemia (glucose toxicity) Protein glycation  -cell Obesity Insulin resistance “Lipotoxicity” (elevated FFA, TG)

20. Dr.Sarma@works NGT=normal glucose tolerance. Weyer C et al. Diabetes Care. 2000;24:89-94. Insulin Resistance and  -Cell Defect Both Contribute to Diabetes Progression 4-Year Cumulative Incidence of Diabetes N=145 Pima Indians with initial NGT Low High Low Percent 0 10 20 30 40 Insulin Secretion Glucose Disposal

21. Dr.Sarma@works Genetics Environment nutrition obesity exercise RetinopathyNephropathyNeuropathy Blindness Renal failure Insulin resistance Hyperinsulinemia Hypertension Decreased HDL-C Increased TG Atherosclerosis Coronary disease LE amputation Natural History of Type 2 Diabetes Onset of diabetes Disability Death Impaired glucose tolerance Ongoing hyperglycemia Complications

22. Dr.Sarma@works Therapeutic Implications: According to Underlying Causes Insulin resistance Treat insulin resistance Lifestyle: especially obesity Prevent and treat obesity Sub-clinical inflammation Treat obesity Statins, Thiozolidines, etc.

23. Dr.Sarma@works Risk FactorDefining Level Abdominal obesity (Waist circumference) Men Women >90 cm (>40 in) 102 cm >80 cm (>35 in) 88 cm TG 150 mg/dl HDL-C Men Women <40 mg/dl <50 mg/dl Blood pressure 130/85 mm Hg (140/90) Fasting glucose100 mg/dl ( >110) ATP III: The Metabolic Syndrome Diagnosis is established when  3 of these abnormalities are present Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

24. Dr.Sarma@works WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. WHO Metabolic Syndrome Definition 1999: Based on Clinical Criteria Insulin resistance (type 2 diabetes, IFG, IGT)* Plus any 2 of the following: Elevated BP (140/90 or drug Rx) Plasma TG 150 mg/dl HDL <35 mg/dl (men); <40 mg/dl (women) BMI >30 and/or W/H >0.9 (men), >0.85 (women) Urinary albumin >20 mg/min; Alb/Cr >30 mg/g * Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR.

25. Dr.Sarma@works

26. Acanthosis Nigricans In patients with Acanthosis Nigricans with or without DMII, not taking statins or lipid lowering agents check their lipid panel, if their LDL and triglycerides are really low think of cancer. The cancers of the endothelium eat up the cholesterol for energy.

27. Dr.Sarma@works Acanthosis Nigricans

28. Dr.Sarma@works Acanthosis Nigricans

29. Dr.Sarma@works Acanthosis Nigricans

30. Dr.Sarma@works PCOS Chronic ovarian dysfunction found in about 6% of pre-menopausal Amenorrhea/ Dysmenorrhea/ oligomenorrhea, abd. pain androgenic characteristics such as low voice and Hirsutism, Acanthosis, Enlarged ovaries may have multiple small cysts Acne, infertility, seborrhea, Acanthosis, obesity Metabolic syndrome, Insulin Resistance, DMII, CVD, HTN, Dyslipidemia, Infertility. Elevated Luteinizing hormone Low normal FSH, May have elevated insulin levels Low dose hormonal contraceptives, and depo-provera ￪ IR. Rx. of the co morbidities such as obesity, insulin resistance, MS

31. Dr.Sarma@works NAFLD There are severe fatty changes in liver USG is diagnostic No history of alcoholism This reflects fat deposition intra-abdominally Non alcoholic fatty liver disease (NAFLD)

32. Dr.Sarma@works Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetes Coronary Heart Disease Type 2 Diabetes High LDL-C Metabolic Syndrome

33. Dr.Sarma@works Conversion Status at Follow-up Diabetes (n=18)Normal (n=490)P BMI (kg/m 2 ) 28.2  1.127.2  0.2.472 Centrality* 1.38  0.091.16  0.2.472 TG (mmol) 1.83  0.121.26  0.10.006 HDL-C (mmol) 1.14  0.071.28  0.02.045 SBP (mm Hg) 116.8  3.0108.8  0.8.004 Fasting glucose (mmol) 5.28  0.15.00  0.02.032 Fasting insulin (pmol)157  2781  5.006 Increased Metabolic Syndrome in Pre-diabetic Subjects: Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status at 8 Year Follow-up - San Antonio Heart Study Haffner SM et al. JAMA 1990;263:2893-2898.

34. Dr.Sarma@works Non-diabetic throughout the study Prior to diagnosis of diabetes Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Nurses’ Health Study Copyright © 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; 1129-1134 Reprinted with permission from The American Diabetes Association. Relative Risk 1 2.82 3.71 5.02 After diagnosis of diabetes Diabetic at baseline

35. Dr.Sarma@works Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic Subjects: Helsinki Policemen Study Years 5102001525 Pyörälä M et al. Circulation 1998;98:398-404. Log rank: Overall P =.001 Q5 vs. Q1 P <.001 Q1 Q2 Q3 Q4 Q5 Proportion without Major CHD Event 0

36. Dr.Sarma@works HOMA-IR Q1Q2Q3Q4Q5 HDL-C (mg/dl)51.749.347.845.041.2 LDL-C (mg/dl)115.7119.3125.0128.1124.8 Cholesterol (mg/dl)188.0191.6197.9200.8199.0 Triglyceride (mg/dl)105.7116.6129.7145.4187.2 Systolic BP (mm Hg)114.9116.5118.3119.3123.0 Diastolic BP (mm Hg)69.070.471.973.175.4 CVD Risk Factors across HOMA-IR Quintiles San Antonio Heart Study (Phase II) All p(trend) < 0.0001; quintile cut points: 1.0, 1.6, 2.5, 4.8 Adjusted for age, sex, ethnicity Copyright © 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; 1177-1184 Reprinted with permission from The American Diabetes Association.

37. Dr.Sarma@works 40–49 Prevalence of NCEP Metabolic Syndrome NHANES III by Age Ford ES et al. JAMA 2002;287:356-359. Prevalence, % 2070+ 20–70+ Age, years 20–29 3039 30–3950–59 6069 60–69 70 Men Women 24% 23% 8% 6% 44% 44%

38. Dr.Sarma@works Prevalence of the NCEP Metabolic Syndrome NHANES III by Sex and Race/Ethnicity Prevalence, % Men Ford ES et al. JAMA 2002;287:356-359. Women White African American Mexican American Others 25% 16% 28% 21% 23% 26% 36% 20%

39. Dr.Sarma@works Prevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+ CHD Prevalence % of Population = No MS/No DM 54.2% MS/No DM 28.7% DM/No MS 2.3% DM/MS 14.8% 8.7% 13.9% 7.5% 19.2% Alexander CM et al. Diabetes 2003;52:1210-1214..

40. Dr.Sarma@works ATP III Metabolic Syndrome: Therapeutic Implications Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome Therefore, prevent development of obesity in the general population Also, treat obesity in the clinical setting (NHLBI/NIDDK Obesity Education Initiative)

41. Dr.Sarma@works Variable Odds Ratio Lower 95% Limit Upper 95% Limit Waist circumference1.130.851.51 Triglycerides1.120.711.77 HDL cholesterol*1.741.182.58 Blood pressure*1.871.372.56 Impaired fasting glucose0.960.601.54 Diabetes*1.551.072.25 Metabolic syndrome0.940.541.68 Different Components of the NCEP Metabolic Syndrome Predict CHD: NHANES *Significant predictors of prevalent CHD Prediction of CHD Prevalence using Multivariate Logistic Regression Copyright © 2003 American Diabetes Association From Diabetes, Vol. 52, 2003; 1210-1214 Reprinted with permission from The American Diabetes Association.

42. Dr.Sarma@works BMI per kg/m 2 HDL-C per mg/dl ↓ SBP per mm Hg FPG per mg/dl Different Components of NCEP Metabolic Syndrome Predict Diabetes San Antonio Heart Study Stern MP et al. Ann Intern Med 2002;136:575-581. Risk of Type 2 Diabetes per Unit Change in Risk Trait Levels 8% 2% 4% 7%

43. Dr.Sarma@works Must Insulin Resistance be Present for a Patient to Have the Metabolic Syndrome? WHO 1999 clinical definition Yes ATP III 2001 clinical definition No, but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome without insulin resistance WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

44. Dr.Sarma@works WHO Metabolic Syndrome Definition 1999: Therapeutic Implications Focus on insulin resistance as the underlying cause of the metabolic syndrome More emphasis on the genetic basis of the metabolic syndrome rather than obesity Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

45. Dr.Sarma@works Therapeutic Implications of Definition of Metabolic Syndrome If focus is on obesity as underlying cause Prevent and treat obesity If focus is on insulin resistance as underlying cause Treat insulin resistance If focus is on metabolic risk factors Treat individual risk factors

46. Dr.Sarma@works Criteria for Comparing Different Definitions of Metabolic Syndrome Risk of: CHD DM Relation to: Insulin resistance Obesity Prevalence in community could differ by race How simple is the definition?

47. Dr.Sarma@works Intensity of Therapy Should be Proportionate to Level of Risk What is the impact of the metabolic syndrome on health outcomes? Cardiovascular disease Type 2 diabetes

48. Dr.Sarma@works Prevention of Type 2 Diabetes: Completed Trials in IGT 31% 58% Metformin Lifestyle changes N Engl J Med 2002 Diabetes Prevention Program (DPP) 3 1. Pan XR et al. Diabetes Care. 1997;20:537-544. 2. Tuomilehto J et al. N Engl J Med. 2001;344:1343- 1350. 3. Knowler WC et al. N Engl J Med. 2002;346:393-403. 4. Chiasson JL et al. Lancet. 2002;359:2072-2077. 25%AcarboseLancet 2002 STOP-NIDDM 4 58%Intensive lifestyle N Engl J Med 2001 Finnish Prevention Study (FPS) 2 31%-46%Diet +/or exercise Diabetes Care 1997 Da Qing IGT and Diabetes Study 1 Results (risk ↓ ) TreatmentJournal/YearTrial

49. Dr.Sarma@works Cardiovascular Disease Mortality Increased in the Metabolic Syndrome: Kuopio Ischemic Heart Disease Risk Factor Study Lakka HM et al. JAMA 2002;288:2709- 2716. Cumulative Hazard, % 0 26812 Follow-up, years YES Metabolic Syndrome: NO Cardiovascular Disease Mortality RR (95% CI), 3.55 (1.98–6.43) 410

50. Dr.Sarma@works NCEP Met SynWHO Met Syn Total Population All Cause1.43 (1.10–1.87)1.25 (0.96–1.63) CVD2.55 (1.75–3.72)1.64 (1.13–2.37) Disease Free* All Cause1.11 (0.74–1.67)0.87 (0.57–1.33) CVD2.04 (1.14–3.63)0.77 (0.38–1.55) Cox Proportional Hazard Ratios (and 95% CI) Predicting All-Cause & Cardiovascular Mortality San Antonio Heart Study 14-Year Follow-up Hunt KJ et al. Diabetes 2003;52:A221-A222. * Those without diabetes, cardiovascular disease, or cancer. Adjusted for age, gender, and ethnic group.

51. Dr.Sarma@works Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Resistant Subjects: IRAS % in Lowest Quartile of S i Hanley AJ et al. Diabetes 2003;52:2740-2747. NeitherNCEP OnlyWHO OnlyBoth Overall Hispanics Non-Hispanic whites African Americans

52. Dr.Sarma@works Relative Risk CRP Adds Prognostic Information at All Levels of Risk as Defined by the Framingham Risk Score <1. 0 hs-CRP (mg/L) Framingham 10-Year Risk (%) 1.0–3.0 >3. 0 Ridker PM et al. N Engl J Med 2002;347:1557-1565. 10+5–92–40–1 Copyright © 2002 Massachusetts Medical Society. All rights reserved. Adapted with permission.

53. Dr.Sarma@works Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: IRAS CRPWBCFibrinogen BMI0.40‡0.17‡0.22‡ Waist0.43‡0.18‡0.27‡ Systolic BP0.20‡0.08*0.11† Fasting glucose0.18‡0.13‡0.07* Fasting insulin0.33‡0.24‡0.18‡ SiSi –0.37‡–0.24‡–0.18‡ Festa A et al. Circulation 2000;102:42–47. *P<0.05, †P<0.005, ‡P<0.0001 CRP=C-reactive protein; IRS=insulin-resistance syndrome; WBC=white blood cell count.

54. Dr.Sarma@works 0 Mean Value of Log CRP Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, Hypertension): IRAS Festa A et al. Circulation 2000;102:42–47. Number of Metabolic Disorders 1234

55. Dr.Sarma@works FibrinogenCRPPAI-1 Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: IRAS Incidence, % 1st Festa A et al. Diabetes 2002;51:1131-1137. 2nd3rd4thQuartiles : P=0.06P=0.001P=0.001

56. Dr.Sarma@works The Effect of Rosiglitazone on CRP Haffner SM et al. Circulation 2002;106:679-684. 8 mg/d Rosiglitazone 8 mg/d 4 mg/d Rosiglitazone 4 mg/d Change from Baseline to Week 26, % Difference = –26.8 (95% CI: –39.7, –21.8) Placebo Difference = –21.8 (95% CI: –34.7, – 5.6) n=95n=124n=134

57. Dr.Sarma@works The Effect of Rosiglitazone on IL-6 Haffner SM et al. Circulation 2002;106:679-684. 8 mg/d Rosiglitazone 8 mg/d 4 mg/d Rosiglitazone 4 mg/d Difference = –1.9 (95% CI: –11.3, 9.3) Placebo Difference = 0.0 (95% CI: –9.0, 10.0) Change from Baseline to Week 26, % n=91n=120n=132

58. Dr.Sarma@works hs-CRP (mg/L) Reduction of CRP Levels with Statin Therapy (n=22) Jialal I et al. Circulation 2001;103:1933-1935. * * * Atorvastati n (10 mg/d) Simvastatin (20 mg/d) Pravastatin (40 mg/d) Baseline * p<0.025 vs. Baseline

59. Dr.Sarma@works Insulin resistance is related to increased PAI-1, fibrinogen, and CRP levels in all sections Increased levels of PAI-1, CRP, and fibrinogen predict the development of type 2 diabetes. In some analyses, these associations are independent of obesity and insulin resistance Rosiglitazone, a TZD, decreases levels of PAI-1, CRP, and MMP-9 Summary

60. Dr.Sarma@works Does Lipid and Blood Pressure Therapy Work in Subjects with the Metabolic Syndrome? Diabetic subjects Blood pressure: YES Statin therapy: YES Non-diabetic non lipid subjects Little data available

61. Dr.Sarma@works StudyDrugNo. CHD Risk Reduction Overall CHD Risk Reduction in Diabetics Primary Prevention AFCAPS/TexCAPSLovastatin15537%43% (NS) HPSSimvastatin291224%33% (p=.0003) Secondary Prevention CARE Pravastatin58623%25% (p=.05) 4SSimvastatin20232%55% (p=.002) LIPIDPravastatin78225%19% 4S ReanalysisSimvastatin48332%42% (p=.001) HPSSimvastatin198124%15% CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses Downs JR et al. JAMA 1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyörälä K et al. Diabetes Care 1997;20:614-620. | LIPID Study Group. N Engl J Med 1998;339:1349-1357. | Haffner SM et al. Arch Intern Med 1999;159:2661- 2667.

62. Dr.Sarma@works Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/TotalResults SHEP583/4736Beneficial GISSI-32790/18,131Beneficial Syst-Eur492/4695Beneficial HOT1501/18,790Beneficial UKPDS1148Beneficial CAPPP572/10,985Beneficial Curb JD et al. JAMA 1996;276:1886-1892. | Zuanetti G et al. Circulation 1997;96:4239-4245. | Staessen JA et al. Am J Cardiol 1998;82:20R–22R. | Hansson L et al. Lancet 1998;351:1755-1762. | UKPDS Group. BMJ 1998;317:703-713. | Hansson L et al. Lancet 1999;353:611-616.

63. Dr.Sarma@works Isolated  LDL-C RR=0.86 (0.59–1.26) 221 “Metabolic Syndrome” in 4S Event Rate, % Ballantyne CM et al. Circulation 2001;104:3046-3051. Simvastatin Placebo 237261284 18.0 20.3 19.0 36.9 Lipid Triad RR=0.48 (0.33–0.69)

64. Dr.Sarma@works Hb A1 c <6.5% Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with Micro-albuminuria): Steno-2 Patients Reaching Intensive- Treatment Goals at Mean 7.8 y, (%) Gæde P et al. N Engl J Med 2003;348:383-393. Intensive Therapy Cholesterol <175 mg/dl Triglyceride <150 mg/dl Systolic BP <130 mm Diastolic BP <80 mm Conventional Therapy P=0.06 P<0.001 P=0.19 P=0.001 P=0.21 Copyright © 2003 Massachusetts Medical Society. All rights reserved.

65. Dr.Sarma@works Composite Endpoint of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for PAD STENO-2 Primary Composite Endpoint (%) Months of Follow-up Gæde P et al. N Engl J Med 2003;348:383-393. 0 2448609636847212 Conventional Therapy Intensive Therapy P=0.007 Hazard ratio = 0.47 (95% CI, 0.24–0.73; P=0.008) Copyright © 2003 Massachusetts Medical Society. All rights reserved.

66. Dr.Sarma@works FACTS ABOUT FATS WE EAT SaFA : Saturated fatty acids Coconut, Red meat, palm oil, butter, ghee, vanaspati, bakery products TrUFA : Trans unsaturated fatty acids Vanaspati, margarine, crispy fried food, buscuits, MUFA : Mono unsaturated fatty acids Olive oil, canola, Nuts PUFA : Poly unsaturated fatty acids Sunflower oil Omega 3 fatty acids – EPA, DHA, AA – Fish oils Reusing cooking oil – great peril

67. Dr.Sarma@works FAT FACTS NameSAFA %MUFA %PUFA % Chol. mg% Canola oil65528 0 Safflower81167 0 Sunflower101860 0 Olive oil12667 0 Sesame oil133638 0 Groundnut154129 0 Palm oil45333 0 Red meat463810 93 mg% Butter/Ghee48274 207 mg% Coconut oil7951 0

68. Dr.Sarma@works We are What We Eat !! CHO – 60 %, Not simple CHO, Complex CHO Protein intake must be at least 15% of calories Pulses, legumes, sprouts, nuts, milk proteins Fats – quantity ↓, quality more of MUFA & PUFA, O3F Fresh vegetables regular diet – fibre Plenty of whole fruits – not juices – pentoses, fibre, vit Avoid junk foods – crispy, crunchy, colas, fast foods

69. Dr.Sarma@works What should I take home ? Metabolic syndrome is a hidden volcano We need to evaluate every one above 25 years of age for MS All those with any one manifestation should be screened for the rest of the components Waist circumference, IR, Dys. Lipidemia There are effective Rx stategies This MS is the “PRE” for DMII and CHD We should not wait till these killers develop

70. Dr.Sarma@works Metabolic Syndrome Therapeutic Objectives To reduce underlying causes Overweight and obesity Physical inactivity To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

71. Dr.Sarma@works Management of Overweight and Obesity Overweight and obesity: lifestyle risk factors Direct targets of intervention Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors Clinical guidelines: Obesity Education Initiative Techniques of weight reduction Metabolic Syndrome

72. Dr.Sarma@works Management of Physical Inactivity Physical inactivity: lifestyle risk factor Direct target of intervention Increased physical activity Reduces metabolic syndrome risk factors Improves cardiovascular function Clinical guidelines: U.S. Surgeon General’s Report on Physical Activity Metabolic Syndrome

73. Dr.Sarma@works Management Strategies 1. TLC – Diet and Weight reduction 2. Physical activity – Abdominal exercises 3. Insulin sensitizers – Metformin 4. Insulin – CHO, Fat metabolizer, anti thrombotic, anti inflammatoty 5. Glitazones – Insulin sensitizer, Anti Inflammatory 6. Statins – Anti inflamma, Anti lipid, Anti thrombotic 7. Aspirin – anti thrombotic, anti inflammatory 8. Nitrates – No increase, vasodilatory

74. Dr.Sarma@works Summary: Metabolic Syndrome The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals subjects with the metabolic syndrome, although not required features of the NCEP metabolic syndrome Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

75. Dr.Sarma@works Hope it is informative enough To set all of us into action