Impact of obesity on cardiometabolic risk: Will we lose the battle?

Impact of Obesity on Cardiometabolic Risk: Will We Lose the Battle? Richard Nesto, MD, FACC, FAHA Chair, Department of Cardiovascular Medicine Lahey Clinic Medical Center, Burlington, MA Associate Professor of Medicine Harvard Medical School, Boston, MA

Effect of Risk Factors and Treatments on Coronary Heart Disease (CHD) Mortality 2000 Deaths prevented or postponed in 2000 68,230 fewer deaths in 2000 Treatments 42% Risk factors: better 58% Risk factors: worse 13% Year 1981 10,000 0 – 10,000 – 20,000 – 30,000 – 40,000 – 50,000 – 60,000 – 70,000 e.g. diabetes, obesity e.g. smoking, cholesterol, blood pressure e.g. secondary prevention, heart failure treatments CHD deaths prevented or postponed by risk factor changes and treatments in England and Wales, 1981 to 2000 2,888 more deaths due to diabetes 2,662 more deaths due to physical inactivity 2,097 more deaths due to obesity Adapted from Unal B et al. Circulation 2004; 109: 1101–7

Increasing Burden of Diabetes on Acute Myocardial Infarction (MI) in New York City: Are We Going Backwards? Rate per 100,000 160 140 100 60 80 ‘ 88 20 Year Days (1,000) ‘ 90 ‘ 92 ‘ 94 ‘ 96 ‘ 98 ‘ 00 ‘ 02 0 40 120 1988-1992 MI Hospitalization For MI Copyright © 2006 American Diabetes Association Adapted from Diabetes ® , Vol. 55, 2006; 768-73 Reprinted with permission from The American Diabetes Association 1998-2002 Diabetes No Diabetes

CARDS: “Low Dose” Atorvastatin Reduces Mortality in Diabetes Hazard ratio = 0.73 (95% CI, 0.52-1.01) Relative risk reduction 27% p=0.059 1 2 3 4 Cumulative hazard (%) Years 4.75 Atorva-statin Placebo Placebo 82 deaths Atorvastatin 61 deaths 0 2 4 6 8 351 332 730 709 1,110 1,094 1,401 1,370 1,418 1,395 1,428 1,410 Residual risk still high Adapted from Cofhoun HM et al. Lancet 2004; 364: 685-96 0

Metabolic Syndrome as a Predictor of Coronary Heart Disease (CHD) and Diabetes in WOSCOPS 14 12 10 6 0 1 % with event 0 3 2 6 4 Years 1 3 2 6 5 12 6 4 2 0 0 Years 4 2 5 4 % with event CHD death/nonfatal myocardial infarction Onset of new type 2 diabetes 8 10 Relative risk Relative risk 24.40 7.26 4.50 2.36 1.00 3.65 3.19 2.25 1.79 1.00 4/5 factors 3 factors 2 factors 1 factor 0 factor 4/5 factors 3 factors 2 factors 1 factor 0 factor Adapted from Sattar N et al. Circulation 2003; 108: 414-9

Metabolic Syndrome and Acute Myocardial Infarction (MI) in the Young (<45 years) AT LAHEY CLINIC: 165 consecutive patients <45 years of age with acute MI and transferred for emergency percutaneous coronary intervention Overall 96 or 59% met National Cholesterol Education Program (NCEP) clinical criteria for metabolic syndrome 8 had prior type 2 diabetes 16 had new diagnoses of type 2 diabetes at MI or within 3 months Mean Framingham 10-year risk score = 5% in metabolic syndrome (in absence of diabetes) 60% had metabolic syndrome and the most common feature was obesity

Best Outcomes Following an Acute Coronary Syndrome (ACS) are Secured by Achieving Low LDL and C-Reactive Protein (CRP) Levels: PROVE-IT N=3,745 Recent ACS Randomized to 40 mg pravastatin vs. 80 mg atorvastatin 3-year follow-up From Ridker PM et al. N Engl J Med 2005; 352: 20-8 Reproduced with permission Copyright © Massachusetts Medical Society. All rights reserved.

Who are the Patients with Higher C-Reactive Protein (CRP) Levels in PROVE-IT after 4 Months of Statin Therapy? 80 90 100 110 120 130 140 NCEP-ATP III cutpoint for metabolic syndrome 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Month 4 Log (CRP) 50 100 150 200 250 300 350 NCEP-ATP III cutpoint for metabolic syndrome 1.0 0.8 0.6 0.4 0.2 0.0 Month 4 Log (CRP) 20 30 40 50 60 70 NCEP-ATP III cutpoint for metabolic syndrome in men 1.4 1.2 1.0 0.8 0.4 0.2 Month 4 Log (CRP) 0.6 NCEP-ATP III cutpoint for metabolic syn-drome in women 60 65 70 75 80 90 NCEP-ATP III cutpoint for metabolic syndrome 1.4 1.2 1.0 0.8 0.4 0.2 Month 4 Log (CRP) 0.6 85 100 110 120 130 NCEP-ATP III cutpoint for metabolic syndrome 0.8 0.6 0.4 0.2 Month 4 Log (CRP) 140 20 25 30 35 WHO cutpoint for obesity 1.0 0.6 0.4 0.0 Month 4 Log (CRP) 40 WHO cutpoint for overweight 0.2 0.8 1.2 Glucose (mg/dl) Triglycerides (mg/dl) HDL (mg/dl) Body mass index (kg/m 2 ) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Month 4 Glucose Month 4 Triglycerides Month 4 HDL Body mass index Month 4 Systolic blood pressure Month 4 Diastolic blood pressure Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46: 1417-24

Serum Concentrations of Adiponectin and Risk of Type 2 Diabetes and Coronary Heart Disease (CHD) in Apparently Healthy Middle-Aged Men 18-year follow-up of a large cohort from Southern Germany Adapted from Koenig W et al. J Am Coll Cardiol 2006; 48: 1369-77 Copyright 2006, with permission from Elsevier 1.29 1.91 1.08 1.17 2.63 1.15 Ref. Ref. T1  5  g/ml T2/T3 > 5  g/ml T1  4.98  g/ml T2/T3 > 4.98  g/ml T1  44.1 mg/dl T2/T3 > 44.1 mg/dl p<0.0001 p=0.60 p=0.63 p=0.0062 p=0.78 p=0.33 T2/T3 > 43.7 mg/dl T1  43.7 mg/dl Adiponectin Hazard ratio (95% CI) HDL cholesterol Incident type 2 diabetes Incident CHD

Impact of Midlife Obesity on Risk for Coronary Heart Disease and Diabetes in Older Age Coronary heart disease mortality Diabetes listed on death certificate 0.1 1.0 10 100 Normal weight Overweight Obese 0.1 1.0 10 100 Low risk Moderate risk Intermediate risk Elevated risk Highest risk Risk category Normal weight Overweight Obese Adapted from Yan LL et al. JAMA 2006; 295: 190-8

Atherosclerosis in Youth is Linked to Obesity and “Early” Insulin Resistance Fatty streaks Men: Age 15-24 Body mass index (kg/m 2 ) >30 25-30 <25 Raised lesions Men: Age 15-24 Aortic Strips <25 25-30 >30 Adapted from McGill HC Jr et al. Circulation 2002; 105: 2712-8 Reproduced with permission Surface area involved (%) <25 25-30 >30 Fatty streaks <25 25-30 >30 Raised lesions Body mass index (kg/m 2 ) Surface area involved (%) Body mass index (kg/m 2 ) Yellow bars indicate panniculus thickness ≤ median for sex and BMI. Blue bars, panniculus thickness > median for sex and BMI.

Risk Factors Identified in Childhood and Decreased Carotid Artery Elasticity in Adulthood - The Cardiovascular Risk in Young Finns Study Cross-sectional study in 3,596 subjects followed from 1980 to 2001 Examined childhood and adult cardiovascular risk factors and relative contribution to coronary artery compliance Assessed body mass index, blood pressure, LDL, HDL, triglycerides, glucose, insulin, smoking Predictors of arterial disease: - Childhood obesity - Blood pressure Adapted from Juonala M et al. Circulation 2005; 112: 1486-93 Carotid artery compliance (%/10 mmHg) Age Carotid artery compliance (%/10 mmHg) Number of childhood risk factors p<0.001 24 27 30 33 36 39 0 1 2 3 or more

Prediabetes is Associated with Accelerated Atherosclerosis: Mexico City Diabetes Study Adjusted for age and sex Adjusted for age, sex, body mass index, total cholesterol, HDL, systolic blood pressure, smoking 0.9 0.8 0.7 0.6 * * * Nondiabetic subjects n=1,127 * Prediabetic subjects n=66 Diabetic subjects n=303 Nondiabetic subjects n=979 Prediabetic subjects n=63 Diabetic subjects n=258 Intima-media thickness (mm) * p<0.05 Common carotid artery Internal carotid artery * * * * Adapted from Hunt KJ et al. Arterioscler Thromb Vasc Biol 2003; 23: 1845-50

Intra-abdominal (Visceral) Fat is a Metabolically Active Organ Infiltrated by Inflammatory Cells Adapted from Tilg H and Moschen AR Nat Rev Immunol 2006; 6: 772-3 and Wellen KE and Hotamisligil GS J Clin Invest 2003; 112: 1785-8 FFA: free fatty acids IL-1  : interleukin-1  IL-6: interleukin-6 JNK: jun N-terminal kinase MCP-1: monocyte chemotactic protein-1 NF-  B: nuclear factor-  B TNF-  : tumor necrosis factor-  VEGF: vascular endothelial growth factor Weight gain Weight gain

Adverse Cardiometabolic Effects of Intra-abdominal (Visceral) Adipocytes Interleukin-6 Adiponectin Leptin Tumor necrosis factor- α Adipsin (Complement D) Plasminogen activator inhibitor-1 Resistin FFA Insulin Angiotensinogen Lipoprotein lipase Lactate C-reactive protein Adapted from Lyon CJ et al. Endocrinology 2003; 144: 2195-200 | Trayhurn P and Wood IS Br J Nutr 2004; 92: 347-55 | Eckel RH et al. The Lancet 2005; 365: 1415-28 ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ Inflammation Hypertension Atherogenic dyslipidemia Insulin resistance and type 2 diabetes Thrombosis Atherosclerosis

Relation Between Adiponectin Levels and Risk of Myocardial Infarction (MI) Relative risk (95% CI) Risk of MI for highest vs . lowest quintile of adiponectin Adjusted for age, date of blood draw, smoking + Adjusted for family history, alcohol, exercise + Adjusted for HbA1c , CRP, HDL, LDL p<0.001 p<0.001 p=0.02 >18,000 men in Health Professionals Follow-up Study free of cardiovascular disease, aged 40-75 years and 6-year follow-up 1.0 0.8 0.6 0.4 0.2 0.0 CRP: C-reactive protein HbA1c: glycosylated hemoglobin Adapted from Pischon T et al. JAMA 2004; 291: 1730-7

Pro-Inflammatory Milieu in Coronary Atheromas of Insulin Resistant Syndromes AGE deposition Receptors (AGEs) Plaque neovascularization Adapted from : 1-Tilg H and Moschen AR Nat Rev Immunol 2006; 6: 772-3 and Wellen KE and Hotamisligil GS J Clin Invest 2003; 112: 1785-8 2- Moreno PR et al. Circulation 2000; 102: 2180-4 3- Cipollone F et al. Circulation 2003; 108: 1070-7 Figures 2 and 3 reproduced with permission AGE: advanced glycation end products IL-1  : interleukin-1  IL-6: interleukin-6 JNK: jun N-terminal kinase MCP-1: monocyte chemotactic protein-1 MMP-2: matrix metalloproteinase-2 MMP-9: matrix metalloproteinase-9 NF-  B: nuclear factor-  B TNF-  : tumor necrosis factor-  2 3 1

Obesity is Independently Associated with Coronary Endothelial Dysfunction in Mild Coronary Artery Disease Higher fasting plasma glucose, higher triglycerides and lower HDL in BMI>25 kg/m 2 groups No difference in coronary diameter between groups with Ach Obesity is associated with endothelial cell dysfunction in coronary microvasculature From Al Suwaidi J et al. J Am Coll Cardiol 2001; 37: 1523-8 Copyright 2001, with permission from Elsevier %  CBF Ach: % change of coronary blood flow in response to acetylcholine BMI: body mass index %  CBF Ach p=0.009 <25 25-30 >30 BMI (kg/m 2 ) n=397

Body Mass Index (BMI): Risk Factor for Unstable Angina and Myocardial Infarction (MI) in Angiographically Confirmed CAD N=382 Adapted from Wolk R et al. Circulation 2003; 108: 2206-11 Reproduced with permission Obesity is associated with a more malignant form of CAD UNIVARIATE analysis: BMI, C-reactive protein, blood pressure, prior MI, insulin resistance, fibrinogen, and CAD extent as predictors of unstable angina MULTIVARIATE analysis: BMI an independent predictor of unstable angina with odds ratio of 1.49 CAD: coronary artery disease 20 25 30 35 40 BMI (kg/m 2 ) Odds ratio n=382

Obesity is a Dominant Risk Factor for Cardiovascular Disease Across All Age Groups Factor Analysis of Clustered Cardiovascular Risks in Adolescence: Obesity is the Predominant Correlate of Risk Among Youth Association of Intra-abdominal (Visceral) Adipose Tissue with Incident Myocardial Infarction in Older Men and Women The Health, Aging and Body Composition Study Goodman E et al. Circulation 2005; 111: 1970-7 Nicklas BJ et al. Am J Epidemiol 2004; 160: 741-9

Impact of obesity on cardiometabolic risk: Will we lose the battle?

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Impact of obesity on cardiometabolic risk: Will we lose the battle?