1. Health Risks and Comorbid Conditions

2. Outline Overview of the Metabolic Syndrome Risks of Obesity and the Metabolic Syndrome Specific Health Risks Answers to Questions & Summary

3. Question # 1 Which of the following is not part of the Metabolic Syndrome? 1.High HDL-cholesterol (> 50 mg/dL) 2.High blood pressure (> 130/85) 3.High Triglyceride (> 150 mg/dL) 4.Impaired fasting glucose (100-126 mg/dL) 5.Increased waist circumference [> 88cm (F) 102cm (M)]

4. Development of the Concept 1904 - Life insurance data 1947 - Vague introduces adipomuscular ratio 1967 - Crepaldi insulin resistance and disease 1970 - Feldman Epidemiological relation 1982 - Ratio of waist to hip circumference related to morbidity and mortality in 2 separate laboratories 1988 - Reaven describes Syndrome X

5. Abdominal Obesity Abdominal Adiposity Courtesy of Steven Smith, M.D. Visceral Subcutaneous

6. Body Fat Distribution and Glucose Tolerance Kissebah JCEM 1982;54:254-260. Upper BodyLower BodyControl

7. Visceral Obesity and Risk of Dyslipidemia Despres JP, et al. Arteriosclerosis. 1990;10:497-511. Obese: Level of deep abdominal fat Variable Nonobese (n = 25) Low (n = 10) High (n = 10) % Body fat28.0 ± 5.647.0 ± 6.449.8 ± 3.2 Deep abdominal fat area (cm 2 )50.3 ± 16.8107.0 ± 33.4186.7 ± 36.8 TG (mmol/L)0.79 ± 0.351.47 ± 0.792.57 ± 2.41 CHOL (mmol/L)4.59 ± 0.885.18 ± 0.935.65 ± 1.23 LDL CHOL (mmol/L)3.00 ± 0.873.56 ± 0.923.81 ± 1.10 HDL CHOL (mmol/L)1.36 ± 0.241.25 ± 0.180.96 ± 0.12 Fasting insulin (pmol/L)39.0 ± 12.491.5 ± 59.9150.3 ± 57.3 Glucose area ([mmol/L/180 min] x 10 3 ) 10.7 ± 0.191.14 ± 0.221.40 ± 0.19 Insulin area ([pmol/L/180] x 10 3 )46.6 ± 19.482.1 ± 48.3121.0 ± 39.5

8. Metabolic Syndrome: NCEP ATP III JAMA 2001;285:2486-2497. Risk FactorCut-Points Central Adiposity M (waist)> 40 in> 102 cm F> 35 in> 88 cm Triglycerides≥ 150 mg/dL≥ 7.1 mmol/L HDL-C M< 40 mg/dL< 0.9 mmol/L F< 50 mg/dL< 1.0 mmol/L Blood Pressure≥ 130/≥ 85 mm Hg Fasting Glucose≥ 110 (100) mg/dL≥ 6.1 mmol/L

9. Age-Adjusted Prevalence of the Metabolic Syndrome Ford. JAMA 2002;287:356-9. Among 8814 Adults Age > 20

10. Characteristics of the Metabolic Syndrome Abdominal obesity Glucose intolerance High triglycerides Low HDL-cholesterol High blood pressure Insulin resistance Microalbuminuria Small dense LDL Inflammatory markers Thrombotic factors Endothelial dysfunction Hyperuricemia Full members Wannabes

11. Central Fat and Lifestyle Health Risk 1.0 0.95 1.0 0.95 Years of follow-up Waist to hip ratio Probability of remaining free of myocardial infarction Probability of survival Lapidus. BMJ 1984;289:1257-61.

12. Outline Overview of the Metabolic Syndrome Risks of Obesity and the Metabolic Syndrome Specific Health Risks Answers to questions & Summary

13. Excess fat stores GenesEnvironment ActivityFood Intake Diseases due to increased fat cell size & visceral fat Stigma Sleep apnea Osteoarthritis Diabetes GB Disease NAFLD CVD Cancer Diseases due to increased fat mass Pathogenesis of Health Problems Associated with Obesity

14. Angiotensinogen Fat Cell Fat Cell Free Fatty Acids Lactate Leptin Adipsin (ASP) (complement ( 3a ;D) Lipoprotein Lipase (LPL) Lipoprotein Lipase (LPL) IL-6 Cholesterolester Transfer Protein (CETP) Prostacyclin Plasminogen Activator Inhibitor (PAI-1) TNF-  Phospholipid Transfer Protein (PLTP) Adiponectin Prostaglandin Monobutyrin Galectin-12 The Fat Cell is an Endocrine Cell

15. Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Coronary heart disease Diabetes Dyslipidemia Hypertension Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gall bladder disease Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis Gout Medical Complications of Obesity Idiopathic intracranial hypertension Stroke Cataracts Severe pancreatitis

16. Outline Overview of the Metabolic Syndrome Risks of Obesity and the Metabolic Syndrome –Mortality –Morbidity Specific Health Risks Answers to questions & Summary

17. Question # 2 Which of the following is NOT an estimate of excess deaths from obesity? 1.450,000 2.365,000 3.325,000 4.275,000 5.112,000

18. BMI and Mortality by Ethnic Group The American Cancer Society Study Calle NEJM 1999;341:1097.

19. Relative Risk of Death by BMI Levels from the NHANES I, II, & III Surveys BMI LevelRelative Risk by Age Category 25-5960-69≥ 70 < 18.51.382.301.69 18.5 to < 251.00 25 to < 300.830.950.91 30 to < 351.201.131.03 ≥ 351.831.631.17 Flegal et al JAMA. 2005;1861.

20. Range of Estimates of Mortality Associated with Overweight AuthorYear Estimated excess deaths Foege & McGinnis1993300,000 Fontaine et al1999 275,000 to 325,000 Mokdad et al2004365,000 Flegal et al NHANES I 2005112,000

21. Overweight* (BMI 25 - 29.9) Obese* (BMI > 30) Female (non-smoker, 40 years of age) 3.29 y7.08 y Male (non-smoker, 40 year of age) 3.05 y5.82 y Obesity Decreases Life Expectancy: The Framingham Study Peeters Ann Int Med 2003;138:24-32. * Compared to a BMI 18.5-24.9 kg/m 2

22. Question # 3 Which disease has the highest risk in association with obesity? 1.Breast cancer 2.Diabetes 3.Cardiovascular disease 4.Osteoarthritis 5.Kidney stones

23. Outline Overview of the Metabolic Syndrome Risks from Obesity and Metabolic Syndrome –Increased mortality –Increased morbidity Specific Health Risks Answers to Questions & Summary

24. Relationship Between BMI and Comorbidities Is Positive, Even in the “Normal” Range Willett WC, et al. N Engl J Med. 1999;341:427-434. Body Mass Index (kg/m 2 ) Relative Risk WomenMen 4 6 5 3 2 1 0 < 21 2223 24252627 28 2930 Body Mass Index (kg/m 2 ) 4 6 5 3 2 1 0 < 212223 24252627 28 29 30 Relative Risk Type 2 diabetes Cholelithiasis Hypertension Coronary heart disease

25. Prevalence (%) by BMI Categories < 21.922 to 23.9 24 to 24.9 25 to 27.9 28 to 29.9 30 to 34.9 35 to 39.9 > 40 High BP18.721.825.331.639.246.655.862 High Chol 33.538.440.944.146.146.744.138.9 Diabetes1.92.22.73.75.68.712.815.2 Arthritis3133.836.338.642.345.148.754.9 Coakley et al IJO 1998;22:958. BMI and Chronic Disease Prevalence in the Nurses Health Study

26. Proportion of Disease Prevalence Attributable to Obesity Type 2 Diabetes57% Gall bladder disease30% Hypertension17% Cardiovascular disease17% Osteoarthritis14% Breast Cancer11% Uterine Cancer11% Colon Cancer11%

27. Age- and Sex-Adjusted Prevalence of Risk Factors for BMI > 30 kg/m 2 Variable NHES 1960-62 NHANES 1971-75 NHANES 1976-80 NHANES 1988-94 NHANES 1999-00 High cholesterol (>6.2 mM) 38.933.131.523.017.9 High BP >140/>90 41.646.535.622.323.7 Diagnosed Diabetes 2.95.96.39.010.1 Gregg et al JAMA 2005;293:1868.

28. Outline Overview of the Metabolic Syndrome Specific Health Risks –Increased risk of diabetes –Increased risk of heart disease –Increased risk of hypertension –Increased risk of cancer –Other increased risks Answers to Questions & Summary

29. Relationship Between BMI and Risk of Type 2 Diabetes Mellitus Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481. Age-Adjusted Relative Risk Body Mass Index (kg/m 2 ) < 23 24 - 24.9 25 - 26.9 27 - 28.9 33 - 34.9 0 25 50 75 100 1.0 2.9 4.3 5.0 8.1 15.8 27.6 40.3 54.0 93.2 < 22 23 - 23.9 29 - 30.9 31 - 32.9 35 + 1.0 1.5 2.2 4.4 6.7 11.6 21.3 42.1 1.0 Men Women

30. Waist CircumferenceRelative Risk of Type 2 DM < 28 inches1.0 28 - 291.2 30 - 312.8 32 - 334.0 34 - 354.8 36 - 375.5 > 386.2 *Controlled for age, family history of diabetes, exercise, smoking, saturated fat intake, calcium, potassium, magnesium, and glycemic index. Nurses’ Health Study: Waist Circumference Directly Related to Risk for Type 2 Diabetes Carey et al. Am J Epidemiol. 1997;145:614.

31. Prevalence Caucasian/African-American (N = 1057) 17% Caucasian/Hispanic (N = 560) 18% Hispanic (N = 31) 45% African-American (N = 97) 47% Prevalence of Type 2 Diabetes Among Diabetic Children in 4 Studies Fagot-Campagna et al. J Pediatr 2000;136:664.

32. GroupRelative Risk Non-diabetic throughout1.0 MI/stroke before diabetes2.8 MI/stroke after diabetes3.7 Diabetes at baseline5.0 Nurses Health Study: Diabetes & MI/Stroke Hu Diab Care 2002;25:1129.

33. Outline Overview of the Metabolic Syndrome Specific Health Risks –Increased risk of diabetes –Increased risk of heart disease –Increased risk of hypertension –Increased risk of cancer –Other increased risks Answers to Questions & Summary

34. BMI Multivariate Relative Risk < 211.0 21 to < 231.2 23 to < 251.3* 25 to < 291.8* > 293.3* BMI and Risk of Coronary Heart Disease in the Nurses Health Study Manson et al NEJM 1995;333:677-85. * = p < 0.05

35. Folsom et al. Arch Intern Med 2000;160:2117. Body Mass Index Tertile 32 3 1 1 2 Relative Risk Waist-Hip Ratio Tertile Abdominal Fat Distribution Increases the Risk of Coronary Heart Disease The Iowa Women’s Health Study

36. Weight Change, kg Body Mass Index (kg/m 2 ) at 18 Years of Age Relative Risk BMI Weight Gain and Cardiovascular Risk Willett et al JAMA. 1995;273:461-5.

37. Body Weight and Weight Gain During Adult Life and Risk of CHD Weight Change CategoryRelative Risk of CHD Loss of 4%1.89 Stable1.00 Gain 4 - 10%1.48 Gain 10 - 15%1.65 Gain 15 - 25%1.48 Gain 25 - 35%1.95 Gain more than 35%2.62 Rosengren et al Europ H J 1999;20:269-277.

38. The Interheart Study: Risk of MI Factor Odds Ratio Population Attributable Risk Abdominal Obesity (WHR)+2.2433.7 Diabetes+3.0812.3 Hypertension+2.4823.4 ApoB/ApoA1+3.8754.2 Smoking*2.2736.4 Psychosocial+2.5128.8 *Adj for Age, Sex & Geography + Adj Age, Sex & Smoking Yusuf et al Lancet 2004;364-352.

39. Incidence per 1000 person years GroupMenWomen Normal Weight5.19.7 Overweight8.610.7 Obese9.914.3 Obesity and the Risk of New Onset Atrial Fibrillation Wang et al JAMA 2004;292:2471-77.

40. Incidence (%) GroupMenWomen Normal Weight5.03.5 Overweight6.03.8 Obese10.06.8 10-Year Cumulative Incidence of Heart Failure in the Framingham Study Kenchaiah et al NEJM 2002;347:305-313.

41. Outline Overview of the Metabolic Syndrome Specific Health Risks –Increased risk of diabetes –Increased risk of heart disease –Increased risk of hypertension –Increased risk of cancer –Other increased risks Answers to Questions & Summary

42. Prevalence of Elevated Blood Pressure by BMI Category BMI RangesMenWomen < 2518.216.6 25 - 2622.521.9 27 - 2925.224.0 > 3038.432.2 NHLBI Evidence Report 1988.

43. Outline Overview of the Metabolic Syndrome Specific Health Risks –Increased risk of diabetes –Increased risk of heart disease –Increased risk of hypertension –Increased risk of cancer –Other increased risks Answers to Questions & Summary

44. Mortality from Cancer in American Men and Women Calle NEJM 2003;348:1625. MenWomen Liver Pancreas Stomach/Esophagus Colon/Rectum Gallbladder Multiple Myeloma Kidney Non-Hodgkin’s Prostate Uterus Kidney Cervix Pancreas/Esophagus Gallbladder Breast Non-Hodgkin’s Liver Ovary Colon/Rectum

45. Outline Overview of the Metabolic Syndrome Overview of Risks Specific Health Risks –Increased risk of diabetes –Increased risk of heart disease –Increased risk of hypertension –Increased risk of cancer –Other increased risks Answers to Questions and Summary

46. Other Increased Risks Kidney stones Complications of pregnancy Sleep disorders Osteoarthritis Stigmatization

47. Relative Risk BMI CategoriesMenWomen < 210.731.15 21 - 22.91.00 23 - 24.90.941.26 25 - 27.41.201.34 27.5 - 29.91.241.75 > 301.331.90 Taylor et al JAMA 2005;293:455-462. Body Mass Index and the Relative Risk of Symptomatic Kidney Stones

48. Pregnancy Complications in Obese and Overweight Nulliparous Women BMI Categories Complications< 20 20 to 24.9 25 to 29.9>30 Gestational Diabetes1.01.32.45.2 Preeclampsia1.01.32.03.3 Eclampsia1.01.42.03.0 Caesarean1.01.31.82.7 Baeten et al Am J Pub Health 2001;91:436-440.

49. Moderate Weight Change and Sleep Disordered Breathing Weight Change (%) Apnea-Hypopnea Index (Events/hour) - 20 kg- 48 10 kg- 26 - 5 kg- 14 5 kg 15 10 kg 32 20 kg 70 Peppard et al JAMA 2000;284:3015-3021.

50. Adjusted Odds Ratio for Osteoarthritis by Tertiles of BMI Tertiles of BMIHandHipKnee 1111 25.43.43.8 38.31.49.3 Oliveria et al Epidemiology 1999;10:161.

51. BMI and Physical Functioning (SF-36) The Nurses Health Study BMI CategoriesRelative Risk < 21.90.94 22 - 23.91.00 24 - 24.91.05 25 - 27.91.23 28 - 29.91.49 30 - 34.91.66 35 - 39.92.08 > 403.08 Coakley et al IJO 1998;22:958-963.

52. Outline Overview of the Metabolic Syndrome Risks of Obesity and the Metabolic Syndrome Specific Health Risks Answers to Questions & Summary

53. Question # 1 Which of the following is not part of the Metabolic Syndrome? 1.High HDL-cholesterol (> 50 mg/dL) 2.High blood pressure (> 130/85) 3.High Triglyceride (> 150 mg/dL) 4.Impaired fasting glucose (100-126 mg/dL) 5.Increased waist circumference [> 88cm (F) 102cm (M)]

54. Question # 1 Which of the following is not part of the Metabolic Syndrome? 1.High HDL-cholesterol (> 50 mg/dL) 2.High blood pressure (> 130/85) 3.High Triglyceride (> 150 mg/dL) 4.Impaired fasting glucose (100-126 mg/dL) 5.Increased waist circumference [> 88cm (F) 102cm (M)]

55. Question # 2 Which of the following is NOT an estimate of excess deaths from obesity? 1.450,000 2.365,000 3.325,000 4.275,000 5.112,000

56. Question # 2 Which of the following is NOT an estimate of excess deaths from obesity? 1.450,000 2.365,000 3.325,000 4.275,000 5.112,000

57. Question # 3 Which disease has the highest risk in association with obesity? 1.Breast cancer 2.Diabetes 3.Cardiovascular disease 4.Osteoarthritis 5.Kidney stones

58. Question # 3 Which disease has the highest risk in association with obesity? 1.Breast cancer 2.Diabetes 3.Cardiovascular disease 4.Osteoarthritis 5.Kidney stones

59. Summary The metabolic syndrome defined as central adiposity, hypertension, impaired fasting glucose and dyslipidemia is a major risk factor for heart disease and diabetes Obesity shortens life and increases the number of excess deaths Diabetes, heart disease, osteoarthritis, cancer, kidney stones, complications of pregnancy, sleep apnea and impaired physical functioning are all associated with obesity