The Metabolic Syndrome

The Metabolic Syndrome The Metabolic Syndrome: A Constellation of CHD Risk Factors • Abdominal obesity* • Atherogenic dyslipidemia • Elevated blood pressure • Insulin resistance  glucose intolerance • Prothrombotic state: increased fibrinogen, and PAI-1 • Proinflammatory state: increased CRP *Abdominal obesity: men  102 cm; women  88 cm NCEP ATP III. Circulation. 2002;106:3143-3421. Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G. The Metabolic Syndrome • Incidence is rapidly increasing in the US and other countries; related to increasing obesity • The metabolic syndrome enhances the risk for CHD at any given LDL-cholesterol level • Has been compared to cigarette smoking as an equal partner to premature CHD NCEP ATP III. Circulation. 2002;106:3143-3421. The Kuopio Ischaemic Heart Disease Risk Factor Study Objective: To assess the association of the metabolic syndrome with cardiovascular and overall mortality, using recently proposed definitions and factor analysis Design: A population-based, prospective cohort study of 1209 Finnish men, aged 42 to 60 years at baseline (19841989), who were initially without cardiovascular disease (CVD), cancer, or diabetes. Follow-up continued through December 1998 Main Outcome Measures: Death due to coronary heart disease (CHD), CVD, and any cause among men with vs without the metabolic syndrome, using 4 definitions based on the National Cholesterol Education Program (NCEP) and the World Health Organization (WHO) Lakka H-M, et al. JAMA. 2002;288:2709-2716. The Kuopio Ischaemic Heart Disease Risk Factor Study: Modified Definitions NCEP Definition WHO Definition At least 3 of the following: Hyperinsulinemia (upper quartile of nondiabetic) or fasting glucose • Fasting plasma glucose 110 mg/dL  110 mg/dL AND at least 2 of the • Abdominal obesity: definition with following: waist • Abdominal obesity: men:  102 cm women:  88 cm • Serum TG  150 mg/dL • Serum HDL-C, men  40 mg/dL women  50 mg/dL (1) waist-to-hip ratio, men  90 cm and women  85 cm or BMI  30 kg/m2; or (2) waist girth  94 cm • Blood Pressure  130/85 mm Hg or medication • Dyslipidemia: Serum TG  150 mg/dL, HDL-C, men  35 mg/dL and women  39 mg/dL • Blood Pressure  140/90 mm Hg or medication Lakka H-M, et al. JAMA. 2002;288:2709-2716. NCEP ATP III. Circulation. 2002;106:3143-3421. Baseline Characteristics of All Men Without Initial CVD, Cancer, and Diabetes, and Those Who Died of CHD, CVD, and Any Cause Characteristic Age, mean (SD), y Family history of CHD, No. (%) Hypertension, No. (%) Body mass index, mean (SD) Waist-hip ratio, mean (SD) Waist circumference, mean (SD), cm Serum LDL-C, mean (SD), mg/dL Serum HDL-C, mean (SD), mg/dL Entire Cohort (n = 1209) 51.5 (5.9) 544 (45) 605 (50) 26.6 (3.3) 0.94 (0.06) 90.1 (9.4) 152 (37) 51 (11) 95 (68-135) CHD Deaths (n = 27) 54.30 (5.2)* 11 (41) 18 (67) 28.6 (4.8)* 0.97 (0.05)* 96.3 (13.5)* 163 (37) 48 (13) 93 (68-183) CVD Deaths (n = 46) 54.1 (5.2)* 22 (48) 34 (74)* 27.6 (4.6)* 0.96 (0.06) 93.4 (12.7)* 156 (39) 52 (13) 77 (60-150) All-Cause Deaths (n = 109) 54.0 (4.9)† 46 (42) 69 (63)* 27.2 (4.0)* 0.96 (0.06)* 93.1 (11.5)* 156 (38) 51 (13) 94 (69-148) Serum triglycerides, median (interquartile range), mg/dL Fasting blood glucose, mean (SD), mg/dL 82 (8) 86 (10)* 84 (9) 84 (9)* †P  0.001, univariate COX proportional hazards regression analyses with death from CHD, CVD, or any cause as the outcome variable * P  0.05, univariate COX proportional hazards regression analyses with death from CHD, CVD, or any cause as the outcome variable Lakka H-M, et al. JAMA. 2002;288:2709-2716. Unadjusted Kaplan-Meier Curve 20 Cumulative Hazard (%) Coronary Heart Disease 20 Mortality Cardiovascular Disease Mortality All Cause Mortality 20 15 RR (95% CI), 3.77 (1.74-8.17) 15 15 RR (95% CI), 3.55 (1.96-6.43) RR (95% CI), 2.43 (1.64-3.61) 10 10 10 5 5 5 0 0 2 0 0 0 2 4 No. at Risk Metabolic Syndrome Yes No 866 288 852 279 8 10 12 6 Follow-up, Y 834 234 292 100 8 10 6 4 Follow-up, Y 852 279 834 234 12 0 2 4 6 8 10 12 Follow-up, Y 292 100 866 288 852 279 834 234 292 100 866 288 Metabolic Syndrome: Yes No Lakka H-M, et al. JAMA. 2002;288:2709-2716. Relative Risk of Death* Adjusted for Age 4.0 3.5 Relative Risk 3.0 † † † † CHD mortality CVD mortality All-cause mortality † † 2.5 2.0 1.5 1.0 0.5 0.0 NCEP NCEP WHO WHO † Waist  102 cm † Waist  94 cm P  0.05; * Subjects with metabolic syndrome (n = 106–179) vs subjects without metabolic syndrome (n = 1037–1103). BMI = body mass index; WHR = waist-hip ratio. WHR  0.90 or BMI  30 Waist  94 cm Lakka H-M, et al. JAMA.2002;288:2709–2716. Relative Risk of Death* Adjusted for Age, Examination Year, LDL Cholesterol, Smoking, and Family History of CHD 4.5 4.0 † Adjusted for: CHD: CVD: All cause: Age only Additional factors Relative Risk 3.5 3.0 † † † † † † † † † 2.5 2.0 1.5 † 1.0 0.5 0.0 WHR  0.90 or BMI  30 * Subjects with metabolic syndrome (n = 106–179) vs subjects without metabolic syndrome (n = 1037–1103); † P  0.05 BMI = body mass index; WHR = waist-hip ratio. Waist  102 cm NCEP Waist  94 cm NCEP WHO Waist  94 cm WHO Lakka H-M, et al. JAMA. 2002; 288: 2709–2716. The Kuopio Ischaemic Heart Disease Risk Factor Study Conclusion: Cardiovascular disease and allcause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes Lakka HM, et al. JAMA. 2002;288:2709-2716. Increasing Obesity in the US • NHANES (1999) data on overweight and obesity (BMI  25 kg/m²) reported – 61% of adults (aged 20–74 years) are overweight or obese  34% are overweight (BMI 25–29.9 kg/m²)  27% are obese (BMI  30 kg/m²) National Health and Nutrition Examination Survey. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf. Accessed January 9, 2003. Trends in Type 2 Diabetes • Diabetes – 15.8 million Americans – 33% increase in prevalence among all adults (1990–1998) – 76% increase in prevalence among adults, age 30–39 years (1990–1999) • Key drivers in increasing prevalence – Rapid growth in high-risk populations – Rapid and continuous growth in obesity – 60% increase in obesity (BMI  30) among adults (1991–2000) – 100% increase in overweight (BMI  25) children/adolescents (1981–2000) Centers for Disease Control. Available at: http://www.cdc.gov/od/oc/media/pressrel/r2k1027a.htm and http://www.cdc.gov/diabetes/projects/cda2.htm. Accessed January 29, 2003. US Census Bureau. Statistical Abstract of the United States: 1999 . Prevalence of The Metabolic Syndrome Among US Adults 45 40 Prevalence (%) 35 30 25 Men Women 20 15 10 5 0 20–29 30–39 40–49 50–59 60–69 70 Age (years) Ford ES, et al. JAMA. 2002;287:356-359. Prevalence of The Metabolic Syndrome in US, by Gender and Race 40 35 Prevalence (%) White African American Mexican American Other 30 25 20 15 10 5 0 Males Females Ford ES, et al. JAMA. 2002;287:356-359. Prevalence of Individual Metabolic Abnormalities Men 50 Women Prevalence (%) 40 30 20 10 0 Ford ES, et al. JAMA. 2002;287:356-359. Causes of The Metabolic Syndrome • • • • Overweight/obesity Physical inactivity Genetics Closely associated with insulin resistance  Underlying cause of diabetes     Reduced HDL-C Elevated triglycerides Hypertension Abdominal obesity NCEP ATP III. Circulation. 2002;106:3143-3421. Insulin Resistance: A Core Defect of The Metabolic Syndrome Hyperglycemia Dysfibrinolysis Hypertension Macrovascular Disease Insulin Resistance Glucose Intolerance Dyslipidemia Endothelial Dysfunction Obesity Adapted from McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718; Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G. Dyslipidemia in the Insulin Resistance Syndrome • Reduced HDL-C • Elevated total TG • Small, dense LDL-C Grundy SM. Am J Cardiol. 1999;83:25F-29F. The Insulin Resistance Syndrome Clinical Manifestations Central obesity Glucose intolerance Hypertension Atherosclerosis Polycystic ovary syndrome Biochemical Abnormalities Carbohydrate: Insulin resistance Hyperinsulinemia Lipid: Fibrinolysis: High TG Increased PAI-1 Low HDL-C Small, dense LDL particles Brunzell JD, Hokanson JE. Diabetes Care. 1999;22(suppl 3):C10-C13; Dunaif A. Endocr Rev. 1997;18:774-800; Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G. Cardiovascular Risk Factors Associated With Insulin Resistance • Increased blood pressure • Hyperinsulinemia • Low HDL cholesterol • High triglyceride levels • Small, dense LDL particles • Increased fibrinogen levels • Increased plasminogen activator inhibitor-1 levels • Increased C-reactive protein and other inflammatory markers • Increased blood viscosity • Microalbuminuria • Increased apolipoprotein B • Endothelial dysfunction McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718. Diagnosis of The Metabolic Syndrome 3 of the following are needed for diagnosis: Risk Factor Abdominal obesity – Men – Women Defining Level Waist circumference  102 cm ( 40 in)  88 cm ( 35 in) Triglycerides HDL cholesterol – Men – Women  150 mg/dL  40 mg/dL  50 mg/dL Blood pressure Fasting glucose  130/85 mm Hg  110 mg/dL NCEP ATP III did not find adequate evidence to recommend routine measurement of insulin resistance (eg, plasma insulin), proinflammatory state, or prothrombotic state in the diagnosis of the metabolic syndrome. NCEP ATP III. Circulation. 2002;106:3143-3421. TLC in The Metabolic Syndrome • Greatest benefit from successful therapeutic lifestyle change (TLC) will occur in persons diagnosed with the metabolic syndrome • Prioritize resources to implement TLC in these patients first NCEP ATP III. Circulation. 2002;106:3143-3421. Does Treating The Metabolic Syndrome Make a Difference? Finnish Diabetes Prevention Study • Design – 522 middle-aged overweight/obese patients (mean BMI 31 kg/m2) – 172 men and 350 women – Mean duration 3.2 years • Intervention group: individualized counseling – Reducing weight, total intake of fat and saturated fat – Increasing intake of fiber, physical activity Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350. Benefit of Treating The Metabolic Syndrome: Finnish Diabetes Prevention Study 25% 20% • After 4 years, risk of diabetes reduced by 58% 15% 10% 5% 0% Intervention Control With Diabetes (%) Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350. Essential Components of TLC Component Recommendation LDL-raising nutrients • Saturated fats • Dietary cholesterol Therapeutic options for LDL lowering • Plant stanols/sterols • Increased viscous (soluble) fiber Total calories 2 g per day 1025 g per day Adjust caloric intake to maintain desirable body weight/prevent weight gain Less than 7% of total calories Less than 200 mg/day Physical activity Include enough moderate exercise to expend at least 200 kcal per day NCEP ATP III. Circulation. 2002;106:3143-3421. Macronutrient Recommendations for the TLC Diet Component Recommendation Polyunsaturated fat Monounsaturated fat Total fat Carbohydrate† Up to 10% of total calories Up to 20% of total calories 25%35% of total calories* 50%60% of total calories* 2030 grams per day Dietary fiber Protein Approximately 15% of total calories *NCEP ATP III allows an increase of total fat to 35% of total calories and a reduction in carbohydrate to 50% for persons with the metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated or monounsaturated fat. †Carbohydrate should derive predominantly from foods rich in complex carbohydrates, including grains, especially whole grains, fruits, and vegetables. NCEP ATP III. Circulation. 2002;106:3143-3421. Drug Treatment of The Metabolic Syndrome • • • • Achieve LDL-C targets Correct atherogenic dyslipidemia NonHDL-C target goal is second priority Consider HDL-C raising NCEP ATP III. Circulation. 2002;106:3143-3421. Treatment of The Metabolic Syndrome • Correct atherogenic dyslipidemia* – Elevated triglycerides – Low HDL-C – Small, dense LDL particles • Correct hypertension • Aspirin for prothrombotic state *LDL-C reduction alone does not result in full benefit NCEP ATP III. Circulation. 2002;106:3143-3421. Treatment of The Metabolic Syndrome (cont.) • Correct insulin resistance – Weight reduction – Increased physical activity – Drugs which decrease insulin resistance have not been proven to reduce CHD risk • Control diabetes mellitus, if present NCEP ATP III. Circulation. 2002;106:3143-3421. Drug Therapy of The Metabolic Syndrome • Decrease small, dense LDL particles – Statins – Nicotinic acid (niacin) – Fibrates (statins may be more effective in reducing total number of LDL particles) • Decrease triglycerides – Fibrates – Omega-3 fatty acids – Nicotinic acid (niacin) – Statins • Increase HDL-C – Nicotinic acid (niacin) – Fibrates, especially if hypertriglyceridemia is present NCEP ATP III. Circulation. 2002;106:3143-3421. Summary of The Metabolic Syndrome • Diagnosis indicates a high-risk patient beyond that classically defined by risk factor assessment • Achieve LDL-C target goals • Control atherogenic dyslipidemia • Weight loss and increased physical activity deserve a high priority NCEP ATP III. Circulation. 2002;106:3143-3421.