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The Metabolic Syndrome: Ready for Prime Time in Clinical Settings? Yuling Hong, MD, PhD, FAHA* Director, Biostatistics and Epidemiology Senior Science and Medicine Advisor American Heart Association The presentation does not necessarily represent the official position of the American Heart Association Outline Evolution of the the Metabolic Syndrome( MetS). Clinical definitions and the implications. Major health consequences of the MetS. Is the metabolic syndrome a useful marker of CHD above and beyond the risk associated with its individual components and other major CVD risk factors? Underlying mechanisms behind the MetS and factors associated with it. Management of the MetS? Future research directions The Metabolic Syndrome, also referred to as Syndrome X, Syndrome X Plus the Insulin Resistance Syndrome, Diabesity, the Big 4, the Deadly Quartet, the, the Reaven Syndrome, is a term for constellation of endogenous risk factors that increase the risk of developing both atherosclerostic vascular disease (ASCVD) and type 2 diabetes mellitus. What is the MetS 1923: Kylin described clustering of hypertension, gout, and hyperglycemia 1988: Reavens Banting lecture at ADA Annual Conference described the term of Syndrome X. 1998: World Health Organization first defined the MetS for clinicians and researchers. 2001: US NCEP ATP III definition for the MetS was released 2005: IDF and AHA/NHLBI definition of the MetS for worldwide use was released Evolution of the MetS Major abnormalities for Syndrome X in Dr. Reaven 1988 Banting Lecture 1. Hypertension 2. Hyperglycemia 3. Glucose intolerance 4. Elevated serum triglycerides 5. Low serum HDL cholesterol Obesity was included and no cut-off points for these abnormalities. Proposed MetS Definitions WHO (1998) Insulin resistance DM / IGT / IFG 2 or more of 1)Obesity W/H ratio:0.9(m), 0.85(w);BMI: 30 2)Dyslipidemia TG 150; HDL-c110 including DM Proposed MetS Definitions AACE (2003) IGT / IFG 1 or more of 1)Obesity BMI: 30 2)Dyslipidemia TG 150; HDL-c100 or Rx *90/80 for Asician A Prevalence of Components of the MetS* Abdominal obesity 39% Hypertriglyceridemia 30% Low HDL cholesterol 37% High blood pressure or medication use 34% High fasting glucose or medication use 13% u 1 Metabolic Abnormalities: 71% u 2 Metabolic Abnormalities: 44% u 3 Metabolic Abnormalities: 24% u 47 MM US Residents *US adults age 20 and over (1988-1994) Ford ES, et al. JAMA. 2002:287:356-359. Age-Adjusted Prevalence of the MetS: Results from the NHANES III Survey* *Criteria based on ATP III; diabetics were included in diagnosis; overall unadjusted prevalence was 21.8%. Prevalence, % 24.8 16.4 28.3 22.8 25.7 35.6 0 5 10 15 20 25 30 35 40 White 25.7% difference African American Mexican American Men Women 56.7% difference Ford ES, et al. JAMA. 2002;287:356-359. 0 5 10 15 20 25 30 35 40 45 50 20-70+ 20-29 30-39 40-49 50-59 60-69 70 Men Women Increasing Prevalence of NCEP MetS with Age (NHANES III) Age (years) Ford E et al. JAMA. 2002;287:356 (%) Number of publication of the MetS in Medical Literatures Year of publication Number of Publications Anyway in the Citation In the title only 1970 70 13 1980 79 30 1988 203 84 1990 260 91 1995 649 278 2000 1097 466 2004 2381 1180 How is the MetS used by clinicians? On May 11, 2000, The US ICD-9-CM Coordinating and Maintenance Committee created a new ICD code for the MetS. The official name is Dysmetabolic Syndrome In October 2001, the code of 277.7 became available. How is the MetS is used by clinicians? Sixteen and 11 records of the MetS in the 2002 and 2003 NHDS database (327254 and 319530 records) Of 16 records in 2002 3: third-listed Dx 2 each: fourth- and fifth-listed Dx 6: sixth-listed Dx 3: seventh-listed Dx Of 11 records in 2003 1: First-listed Dx 2 each: third- through seventh- listed Dx Ford E. Diabetes Care 2005;28:1808 Major Health Consequences of the MetS Summary of evidence from 15 prospective studies Relative Risk for ATP III MetS definition For all-cause mortality 1.27 (95%CI: 0.90-1.78) For CVD 1.65 (95%CI:1.38-1.99) For DM 2.99 (95%CI:1.96-4.57) Relative Risk for WHO MetS definition For all-cause mortality 1.37 (95%CI: 1.09-1.74) For CVD 1.93 (95%CI:1.39-2.67) For DM 2.60 (95%CI:1.55-4.38) Ford E. Diabetes Care 2005;28:1769 Major Health Consequences of the MetS Summary of evidence from 15 prospective studies Population-attributable fraction for the MetS: 6-7% for all-cause mortality 12-17% for cardiovascular disease 30-52% for diabetes mellitus Ford E. Diabetes Care 2005;28:1769 Major Health Consequences of the MetS Summary of evidence from 15 prospective studies Adjustment scheme None: 3 studies Age only: 4 studies Age, sex: 1 study Age, sex, race: 1 study Age, sex, race, and other major CVD risk factor: 6 studies Age, sex, race, and all major CVD risk factor (ie, Family history, smoking, HBP, high cholesterol, Obesity, physical inactivity, diabetes): none Ford E. Diabetes Care 2005;28:1769 Major Health Consequences of the MetS Summary of results from 11 prospective studies in non-diabetic European men and women Overall hazard ratios for all-cause mortality* 1.44 (95% CI: 1.17-1.84) in men 1.38 (95% CI: 1.02-1.87) in women Overall hazard ratios for cardiovascular mortality* 2.26 (95% CI: 1.61-3.17) in men 2.78 (95% CI: 1.57-4.94) in women *After adjustment for age, BP, cholesterol and smoking Hu G, et al. Arch Int Med 2004;164:1066 What is the Pathophysiology of the MetS? Role of obesity Role of primary insulin resistance Role of physical inactivity Atherogenic diet Role of aging Role of genetic defects in each of the metabolic risk factors How does obesity relate to the MetS? Increased release of NEFA Increased secretion of: TNF alpha, IL-6 Leptin, resistin, visfatin Inflammatory cytokines, PAI-1 Decreased secretion of adiponectin Genetics of the MetS Genetic factors contribute to: Atherogenic dyslipidemia (high TG, high apo B, small LDL, low HDL) Hypertension Hyperglycemia Proinflammatory state Prothromobotic state Common genetic for all the component of the MetS BMI IR TG HDL SBP G E G G G E E E E Genetic and Environmental Architecture of IRS Hong Y et al. AJHG 1997;60:143 Goals and Recommendations for Clinical Management of the MetS No specific drugs for the MetS use only Refer AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke, AHA/ACC Guidelines for Prevention Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7), and the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III) in the US Additional measures reported to be associated with the MetS and in need of more research Abnormal fat distribution General fat distribution Central fat distribution Biomarkers Liver fat contents Myocellular fat Atheogenic dyslipidemia Apolipoprotein B Small LDL particles Triglycerides/HDL-c ratio Dysglycemia Fasting glucose OGTT Hoemonal factors Corticosteroid axis Polycystic ovary syndrome Insulin resitance Fasting insulin/proinsulin HOMA-IR IR by Bergman MIMOD Elevated fasting or OGTT FFA Vascular Dysregulation Endothelial dysfuction Microalluminua Chronic renal disease Proinflammatory state C-reactive protein Inflammatory cytokines Prothrombotic state Fibrinolytic factors (PAI-1, etc) Clotting factor (fibrinogen, etc) Grundy et al. Circulation 2005,112, Modified AddFuture research Assess whether all components of the MetS are equally important and whether some combinations have great risk Need more evidence-based analysis to assess the rationale and value of adding or (replacing) other CVD risk factors (eg, age, CRP, family hx, a direct measure of insulin resistance Require additional basic and clinical research to better understand Pathophysiology from the standpoint of genetics molecular biology and cellular signaling Establish a standard method to measure blood insulin level Conduct clinical trials to conform ASCVD risk reduction from decreasing insulin resistance per see Improve strategies to achieve and sustain long-term weight reduction and increased physical activities Evaluate the cost-effectiveness of various drugs, both alone and in combination therapies Adjusted Hazard Ratios (95% Confidence Interval) of Incident CHD Associated with MetS Clusters The ARIC Study Components Cluster Events/Participants HR (95%CI) Reference Group 86/2804 1 HBP+HG+TG 16/90 5.08 (2.96,8.70) HBP+HG+HDL 19/100 5.68 (3.44,9.37) HBP+HG+WC 36/465 2.77 (1.86,4.13) HBP+TG+HDL 43/269 3.98 (2.75,5.77) HBP+TG+WC 20/285 2.20 (1.35,3.58) HBP+HDL+WC 34/536 2.52 (1.69,3.76) HG+TG+HDL 9/85 2.51 (1.26,5.00) HG+TG+WC 3/65 1.39 (0.44,4.41) HG+HDL+WC 10/162 2.25 (1.17,4.33) TG+HDL+WC 33/497 2.32 (1.55,3.46) HBP+HG+TG+HDL 25/141 4.99 (3.19,7.82) HBP+HG+TG+WC 25/177 4.59 (2.93,7.19) HBP+HG+HDL+WC 39/345 4.45 (3.03,6.53) HBP+TG+HDL+WC 53/528 3.36 (2.38,4.73) HG+TG+HDL+WC 33/231 4.60 (3.08,6.87) HBP+HG+TG+HDL+W C 98/570 6.24 (4.65,8.36) Reference Group=No MetS components HBP = Elevated BP HG = Elevated fasting glucose TG = Elevated triglycerides HDL = Low HDL-Cholesterol level WC = Elevated Waist circumference All 16 possible clusters of MetS components were entered into the models and compared to individuals without any of MetS components (reference group). All models were adjusted for age, race, and sex. Personal communication with Dr. D Liao Conclusions