diabetes type 2 and CVD Adopted from Serena Tonstad MD PhD MPH Raymond Knutsen MD MPH EPDM 566 Epid of CVD NIH 1985 expert panel on obesity Obesity defined as An excess of body fat frequently resulting in impairment of ID: 1045531
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1. Obesity, fat distribution, diabetes type 2 and CVDAdopted from: Serena Tonstad, MD, PhD, MPHRaymond KnutsenMD, MPHEPDM 566 – Epid of CVD
2. NIH 1985 expert panel on obesity Obesity defined as: An excess of body fat frequently resulting in impairment of health Obesity include: OverweightFatnessFat distribution Central (abdominal)Truncal (thorax and abdomen)
3. NIH 1985 expert panel on obesity Fat storage: May be adaptive to needs for energy reserves To ensure survivalNowadays:Mainly detrimental because energy consumption in general exceeds energy expenditure
4.
5. Obesity measures Obesity as a function of height and weight are the two most common measures: Relative weight – weight relative to (% of) “desirable” or “ideal” body weight (%IBW) Body Mass Index (BMI) Height (m)/Weight2 (kg)
6. Obesity measures Obesity may also be viewed in relation to lean body mass: Subscapular skinfold measure
7. WHO Classification of ObesityCLASSBMI (kg/m2)Underweight<18.5Normal18.5–24.9Overweight25–29.9Obese30 Class I30.0–34.9 Class II35.0–39.9 Class III40NIH/NHLBI The Practical Guide. Identification, Evaluation and Treatment of Overweight and Obesity in Adults, October 2000BMI = body mass index
8. Prevalence of obesity has increased dramatically in the US over the past few decades from 26% in 1976-80 to 34% in 1988-91 (NHANES). This trend is observed in all developed countries and represent a potentially huge epidemic of obesity related diseases: Hypertension Diabetes type II CHD Osteoarthritis
9. BMI = body mass indexSource: Ono T, Guthold R, Strong K. WHO Global Comparable Estimates, 2005 http://www.who.int/mediacentre/factsheets/fs311/en/ (Accessed February 2015)WHO Global Estimates - MalesWorldwide 2014: > 1.9 billion adults (39%) aged ≥18 years were overweight. Of these > 600 million (>13%) were obese.
10. WHO Global Estimates - FemalesSource: Ono T, Guthold R, Strong K. WHO Global Comparable Estimates, 2005 http://www.who.int/mediacentre/factsheets/fs311/en/ (Accessed February 2015)BMI = body mass indexWorldwide 2014: > 1.9 billion adults (39%) aged ≥18 years were overweight. Of these > 600 million (>13%) were obese.
11. (*BMI 30)HispanicPrevalence of Obesity* Among U.S. Adults, by Race/Ethnicity, 2006-2008White non-HispanicBlack non-Hispanic
12. Prevalence of Obesity* Among U.S. Adults, by Race/Ethnicity, 2011-2013(*BMI 30)White non-HispanicBlack non-HispanicHispanicSource: Behavioral Risk Factor Surveillance System, CDC
13. Age-adjusted prevalence of obesity (BMI≥30) in Americans ages 20-74 by genderSource: Health, United States, 2013, CDC/NCHS. http://www.cdc.gov/nchs/data/hus/hus10.pdf Circulation 2015;131:e; DOI: 10.1161/CIR.0000000000000152 NHES, 1960-62; NHANES, 1971-74, 1976-80, 1988-94, 1999-2002, 2003-2006, 2009-2012Percent of Popul;ation10.712.212.820.628.133.135.115.716.817.126.034.035.236.4
14. Age-adjusted prevalence of obesity (BMI≥30) in Americans aged ≥20 by race and genderSource: Health, United States, 2013, CDC/NCHS. http://www.cdc.gov/nchs/hus/contents.2013.htm#fig11 Percent of Popul;ationPercent of Popul;ation
15. Age-adjusted prevalence of obesity (BMI≥30) in Americans aged ≥20 by age group and gender. US 2011-2012. Source: CDC/NCHS. NHANES, 2011-2012Percent of Popul;ation1Significant difference from ages 20-392Significant difference from ages 40-59Estimates are age-adjusted for all aged ≥20 by the direct method to the 2000 US census population using age groups 20-39, 40-59, and ≥60.
16. Age-adjusted prevalence of obesity (BMI≥30) in Americans by age group and genderPercent of Popul;ationPercent of Popul;ationSource: CDC/NCHS. NHANES, 2011-2012
17. Am J Clin Nutr. 2004;79:774-9
18. England, 1980-2002 Q J Med. 2004;97:817-25Obesity in:2- to 4-year-olds almost doubled (5%→9%) in 10 years (1989→1998)6-15-year-olds trebled (5%→16%) in 11 years (1990→2001)Adult women nearly trebled (8%→23%) in 22 years (1980→2002)Adult men nearly quadrupled (6%→22%) in 22 years (1980→2002)
19. BMI Notes and Worldwide PrevalenceAt same BMI, women have more body fat than men (but not higher morbidity or mortality)At same BMI, the elderly have more body fat than younger adultsSome athletes have high BMI due to increased muscle massHighest prevalence: Pacific islands, e.g. 79% in NauruLowest prevalence: Rural India, China, Japan, Phillipines
20. Behavioral Causes of Mortality
21. BMI & Education in California
22. Keys to Understanding ObesityHuman beings have a very large storage capacity of fat (lean adult: 35 billion fat cells that each store 0.4-0.6 ug lipids which is equivalent to 100,000 kcal) Gastroenterology 2002;123:882-932In extreme obesity the number of adipocytes is increased to as many as 125 billion fat cells that store 0.8-1.2 ug of lipids which is equivalent to 1,000,000 kcalMost people are susceptible to obesity; very few are resistant
23. St. Jeor, S. T. et al. Circulation 2004;110:e471-e475
24. Estimated Heritability of Adiposity/BMI and of ObesityStudies of Monozygotic Twins Reared Apart (adoption studies) Heritability of adiposity/BMI : 50% to 80%Bell, Nature Reviews Genetics, 2005Studies of Families with obesity (BMI> 30): Relative Risk for obesity: 3 to 10
25. Life Expectancy at age 40:Impact of Excess Body Weight35404550FemalesMalesLife expectancy (years)Peeters et al. Ann Intern Med, 2003;138:24-32Normal 18.5–24.9 kg/m2Overweight 25–29.9 kg/m2Obese 30 kg/m246.343.039.243.440.337.57.1 y5.8 y3.1 y3.3 yFramingham Heart Study
26. Diseases Associated with ObesityObesityDigestive problemsType 2 DiabetesArthritisHypertensionDyslipidemiaCancerStrokeCHDM&M=morbidity and mortalityGastroenterol. 2002;123:882-932.CardiovasculardiseaseMetabolic syndromeCardiac failurePoor wound healingIncreased M&Mafter surgery
27. Studies on Body Weight and CHD Morbidity/Mortality StudyNumber/GenderAge at EntryFollow-up (yrs)Index of ObesityAssoc Obes Index-CHD Am Ca Society(Lew 1975)336,442 M 419,060 F 30 – 8913RelativeweightM: linearF: J-shapedFramingham Heart(Hubert 1983) 2,252 M 2,818 F28 – 6226RelativeWeightLinear (CHD in all);MI in F; SD in MNurses’ Health(Manson 1990) 115,886 F30 – 558BMILinearSeventh Day Adv.Lindsted 1991) 8,828 M52.8(Mean)26BMILinearHarvard Alumni (Lee 1993) 19,297 M46.6(Mean)22 – 26BMILinearGotenburg Study, Mb.1913 (Ohlson 1985) 792 M5413WHR, BMI,skinfold thickLinear for WHR(indep. of BMI)Gotenburg Study, F(Lapidus 1984) 1,462 F38 – 6012WHR, BMI,skinfold thickLinear for WHR(indep. of BMI)Iowa Women’s Study(Folsom 1993)41,837 F55 – 695WHR, BMILinear for WHR(indep. of BMI)SD, sudden death; WHR, waist:hip ratioEd: Manson JE, Ridker PM, Gaziano JM, Hennekens CH. Prevention of Myocardial Infarction (1996), p. 208
28. Which Type of RiskRelative risk: CVD relative risk (RR) = 1.3-2 but the effects are primarily mediated through risk factors; diabetes type 2: RR=5-90Population attributable risk: % of the disease that could be avoided if the risk factor were eliminated (assuming that the risk factor is causal) Absolute risk: The probability of a disease in a population (e.g. Incidence). Does not include risk of the disease in non-exposed individuals, so cannot indicate whether the exposure is associated with increased risk of the disease.
29. Nurses Health Study8 yrs follow-upRisk of non-fatal MI and fatal CHD according toBMI levels.N Eng J Med. 1990;322:882-9Adjusted for age Adjusted for age and smoking
30. Nurses Health Study8 yrs follow-upRisk of MIand fatal CHDassociated withBMI (queteletIndex)Risk increasesmore where otherrisk factors presentEd: Manson JE, Ridker PM, Gaziano JM, Hennekens CH. Prevention of Myocardial Infarction (1996), p. 206
31. Risk increasesSteadily fromBMI of about22.0.N Eng J Med. 1995;333:677-85Nurses Health Study16 yrs follow-up
32. FraminghamStudy26 yrs follow-up Ed: Manson JE, Ridker PM, Gaziano JM, Hennekens CH. Prevention of Myocardial Infarction (1996), p. 209CVD
33. The association withstroke is less strong.Harward Univ. Alumni19,297 men25 yrs follow-upCVD=Cerebrovascular disease = STROKEJAMA. 1993;270:2823-8
34. Honolulu Heart Program7,692 men12 yrsfollow-up Lancet. 1987, April 11:821-3SSF=SubscapularFold=Measure of CentralAdiposity
35. Population Attributable Risks of ObesityStroke (26%)Shortness of breath/sleep apneaCardiovascular disease (14-20%)Gallbladder disease/fatty liver (³14%)Hormonal disturbancesStress incontinenceHyperuricemia and gout (20%)(Hip fracture -4%)Risk factors forcardiovascular disease (7-24%)Diabetes (24-50%)Cancer (3-9%)Skin (sweating, cellulitis)Ostoearthritis/other muskuloskeletal (³12%)Kopelman Nature 2000; 404: 645Bray J Clin Endo & Metab 2004; 89: 2583
36. BMI and Cancer Risk - menRenehan AG et al Lancet 2008; 569.
37. BMI and Cancer Risk - womenRenehan AG et al Lancet 2008; 569.
38. BMI and MortalityA variety of results from studies: Positive Non-significant positive No association Non-significant negative J-shaped U-shaped Inverse associations
39. Possible reasons for variety of results: Failure to control (adjust) for cigarette smoking Inappropriate control /“over-control” for the biological effects of obesity, such as high blood pressure dyslipidemia Failure to eliminate early deaths Even when this is done, results may be inconsistentLength of follow-up: Obesity may take over a decade to impact mortalityBMI and Mortality
40. 0.61.01.41.82.22.63.03.2<18.518.5-20.420.5-21.922-23.423.5-24.925.0-26.426.5-27.928.0-29.930.0-31.932.0-34.9Relative risk of death³35.0 BMI and Mortality in MenCardiovascular diseaseCancerAll other causesBody Mass Index (kg/m2)Calle EE et al. N Engl J Med 1999; 341: 1097-195
41. 0.60.81.01.21.41.61.82.02.22.4<18.518.5-20.420.5-21.922.0-23.423.5-24.925.0-26.426.5-27.928.0-29.930.0-31.932.0-34.935.0-39.9³40.0 BMI and Mortality in WomenBody Mass Index (kg/m2)Calle EE et al. N Engl J Med 1999; 341: 1097-195Cardiovascular diseaseCancerAll other causesRelative risk of death
42. Body Fat Location and CHD WHERE overweight is located is important for risk of CHD:A high Waist/Hip ratio indicates “central” adiposity = “upper body”/abdominal adiposity→ ↑ CHD risk (Gotenburg Study, Sweden, Lapidus et al. Br Med J 1984; 289:1257-61)The Waist/Hip ratio is a stronger predictor of CHD than BMI (Nurses Health Study, Rexnode et al. JAMA 1998;280:1843-8)
43. 020406080100120140Abdominal Obesity Increases Risk Independently of BMILow (73.6)Middle (73.7-81.7)High (81.8)Waisttertiles (cm)High(25.2)Middle(22.2-25.1)Low(22.1)BMI tertiles (kg/m2)Age adjusted CHD incidence/100 000 person-yearsRexrode KM et al. JAMA, 1998; 280: 1843-8774655899712811083106Nurses Health Study
44. JAMA. 1998;280:1843-488 years follow-up of 44,702 women, 40-65 years at baseline (1986).
45. JAMA. 1998;280:1843-488 years follow-up of 44,702 women, 40-65 years at baseline (1986).
46. JAMA. 1998;280:1843-488 years follow-up of 44,702 women, 40-65 years at baseline (1986).
47. Paris ProspectiveStudy13 yrs follow-up of1,000 men born in 1913Int J Obesity. 1991;15:53-7
48. IOWA WOMENS STUDY RR for quintile12345P (trend)BMI1.000.760.650.761.03.94WHR1.001.671.862.773.39<.001JAMA. 1993;269:483-7Multivariate adjusted risk of CVD death during 5 years of follow-up ▪ 41,837 Iowa women aged 55-69 years ▪ 234 CVD deaths occurred
49. 12 yrs follow-up of CHD incidence in 1,462 women and 792 menAm J Epid. 1992;135:266-73M:F incidence of CHD is mainly linked to one factor: waist:hip ratio.When adjusting for waist:hip ratio, sex differences in CHD risk disappears. Odds Ratios for 12-year male-female incidence of CVD in Gothenburg, Sweden*ModelFactors for which odds ratio was adjusted Odds Ratio (95% CI)Men aged 54 years vs. women aged 54 yearsMen aged 54 years vs. women aged 50-60 years1None3.2 (1.3-7.5)5.6 (2.5-7.6)2Diastolic blood pressure,Cholesterol, BMI, Smoking3.1 (1.2-8.0)4.2 (2.2-8.1)3Factors in Model 2 plus waist:hip ratio1.1 (0.2-3.5)1.0 (0.4-3.0)4Waist:hip ratio1.4 (0.4-3.6)1.2 (0.5-3.0)*Men, 1967 to 1979; Women, 1968-1969 to 1980-1981
50. Obesity & Risk of MI in 27,000 Participants from 52 Countries: a Case-Control Study27 098 participants in 52 countries (12 461 cases & 14 637 controls) representing several major ethnic groupsThe Interheart Study. Yusuf et al Lancet 2005, 366, 1640Waist-to-hip ratio shows a graded & highly significant association with MI risk worldwideRedefinition of obesity based on waist-to-hip ratio instead of BMI increases the estimate of MI attributable to obesity in most ethnic groups
51. The Interheart Study. Yusuf et al Lancet 2005, 366, 1640
52. Interheart Study: BMI vs Waist/hip & MIYusuf et al Lancet 2005, 366, 1640
53. Interheart Study: Waist and Hip Risks of MIYusuf et al Lancet 2005, 366, 1640
54. Interheart Study: Waist/hip Ratio & MIYusuf et al Lancet 2005, 366, 1640
55. Interheart Study:Ethnic groupsYusuf et al Lancet 2005, 366, 1640
56. Interheart Study: Comparison of Risks of Anthropometric MeasuresYusuf et al Lancet 2005, 366, 1640
57. An Increased Waist:Hip Ratio is,independent of obesity, associated with: Diabetes Elevated Triglycerides Elevated Insulin levels Increased Blood PressureLarsson et al. Am J Epidemiol.1992;135:266-73. Males tend to be of the apple shapeFemales tend to be of the pear shapeThe differences in body shape can, to a large extent, explain the sex differences in CHD risk
58. Max 88cmMax 102cmWaist- (hip ratio)
59. Health Risk in Adults According to BMI and Waist CircumferenceBMI (kg/m2)Normal18.5 - 24.9LeastIncreased riskOverweight25.0 - 29.9IncreasedHigh riskObese≥ 30HighVery High risk 102 cm (Men) 88 cm (Women)≥ 102 cm M ≥ 88 cm W<<Waist Circumference
60. Visceral Fat is Associated with all the CVD Risk FactorsHypertensionDyslipidemiaSexInsulin resistanceLDL particle sizePostprandial hyperlipidemiaCRPThrombogenicityAbdominal obesityOther/direct mechanismsEndothelialdysfunction
61. Festa A, et al. Circulation 2000; 102:42Mean log C-reactive protein 1.6001234Number of metabolic disorders1.41.21.00.80.60.40.21.6CRP in Relation to Metabolic Risk FactorsNon-diabetic population of the Insulin Resistance Atherosclerosis Study All comparisons P = 0.0001 except 2 vs. 4 P < 0.005, and 3 vs. 4 P = nsN = 1,008
62. CauseHigh blood pressureInsulin resistanceLipiddisturbanceEndpoint: CVDIntermediate effects (metabolic syndrome and DM2)Source of Cardiovascular Disease
63. National Cholesterol Education Program Definition 2001 and Modification in 2004Glucose >100 mg/dl (modified later, was 110 mg/dl)Waist > 40 inches (men) or > 35 inches (women) BP > 130/ > 85 mm Hg (or treated for hypertension)Low HDL cholesterol (<40 mg/dl for men and <50 mg/dl for women)Triglycerides >150 mg/dlAbdominalobesityHypertensionDyslipidemiaGlucosedisturbanceThree of five factors
64. Harmonized Metabolic SyndromeRisk FactorDefining LevelAbdominal obesity (waist circumference)MenWomenPopulation and country specificTriglycerides≥1.7 mmol/L (≥150 mg/dL) or useof drugsHDL-CMenWomen<1.0 mmol/L (<40 mg/dL)<1.3 mmol/L (<50 mg/dL) or use of drugsBlood pressure≥130/85 mm Hg or use of antihypertensive medicationFasting glucose≥5.6 mmol/L (≥100 mg/dL)Alberti KG et al. Circulation 2009; 120: 1640-5.Metabolic syndrome is based on presence of 3 or more of these risk determinants
65. Figure 1. Worldwide prevalence of the metabolic syndrome.Potenza M V , Mechanick J I Nutr Clin Pract 2009;24:560-577
66. Risk Factors for Metabolic Syndrome and Insulin ResistanceVisceral obesityGender EthnicityExcess energy intakePhysical inactivityCigarette smokingCertain medicationsStress (what kind?)Fetal malnutrition
67. Insulin resistanceReducedglucosetoleranceEarlydiabetesLatediabetesVisceral adiposityb cell defectLATE complicationsCARDIOVASCULAR DISEASECARDIOVASCULAR DISEASE
68. Diabetes Mellitus - (DM) Two types:Insulin dependent diabetes mellitus (IDDM) (Type I)Non-insulin dependent diabetes mellitus (NIDDM) (Type II) Estimated occurrence:14-16 million diabetics in the USNIDDM - 90%IDDM – 10%. Scandinavia has some of the highest rates.Race:DM is more prevalent among blacks and Hispanics than in whitesUS: Pima indians – NIDDM prevalence 40-50%. Onset in the 30’s to 40’s.
69. Increasing Prevalence of Diabetes Worldwide*ProjectedEstimated prevalence (millions)199420252001501005003002502000100151299*Adapted from Diabetes Atlas 2000. Brussels: International Diabetes Federation.
70. Development of Diabetes type 2Insulin resistance → ↓effect of insulin↓beta cell function → ↓insulin secretion At the onset of diabetes, about 50% of beta cell function is lostSe. Glucose ≥126 mg/dl defines diabetesThis definition is based on the threshold for microvascular complications (neuropathy, nephropahty, retinopathy)
71. Relative Risks for fatal CHD in men and women with/without diabetes Age adjustedWomenMenMultiple adjustedWomenMen3.72.23.12.0Relative riskP value for heterogeneity0.0070.008Relative risk (95% CI)2148Huxley, R. et al. BMJ 2006;332:73-78n=22 studies
72. Diabetes Type 2 and CVD RiskFramingham Heart Study *P < 0.1; †P < 0.05; ‡P < 0.01; §P < 0.001Kannel WB, et al. Am Heart J 1990; 120:672.451236Coronary mortalitySudden deathAngina pectorisMICHDCardiac failureIntermittent claudicationStrokeAny CVD event§*§†§†§†‡ §††Males with diabetesFemales with diabetes‡ Age-adjusted risk ratio(1 = risk for individuals without diabetes) N/A
73. CHD mortality, Diabetes type 2 and History of Myocardial Infarction604020010013578Type 2 DM, no MI (n=890)No DM, no MI (n=1304)Survival (%)Years800246No DM, history of MI (n=69)Both Type 2 DM and MI (n=169)Haffner SM et al. NEJM 1998; 339: 229-234
74. Epidemiological Studies of Weight LossWeight reduction is associated with increased mortality but the relation is confounded by smoking, other diseases, weight regain, loss of bone mass, Yo-yo dietingWe do not have randomized clinical trials of the relation of weight loss to mortality or most morbiditiesWe do have randomized clinical trials showing that lifestyle change/weight loss reduce diabetes type 2Gregg Ann Intern Med 2003;138:383; Cundiff DK. International J Obesity 2006; 30: 1173-5
75. Diabetes Prevention Program: lifestyle change stops progressionDiabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.
76. Finnish Diabetes Prevention Study: Proportion of Subjects Without Diabetes
77. DietPhysical activityAbdominal obesityAfter weightreductionWeight ~ 10 % = Visceral fat RelativelyMoreVisceral fatDeteriorationLipidsImprovementDeterioratedInsulin sensitivity GlucoseImprovedProthromboticfactorsInflammationDeterioratedEndothelialdysfunctionImproved