Metabolic Syndrome Update The Metabolic Syndrome: Overview. Global Cardiometabolic Risk

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1 Metabolic Syndrome Update 21 Marc Cornier, M.D. Associate Professor of Medicine Division of Endocrinology, Metabolism & Diabetes University of Colorado Denver Denver Health Medical Center The Metabolic Syndrome: Overview What is it? Why do we care? How do we define it? How should we manage it? Is there a controversy? Smoking LDL HDL HTN Age Sex Family Diabetes Global Cardiometabolic Risk Inflammation Insulin Resistance Obesity Triglycerides Thrombosis

2 The Metabolic Syndrome: General Clustering of Features Abdominal obesity Atherogenic dyslipidemia Elevated Triglycerides Low HDL-Cholesterol Small dense LDL particles Raised blood pressure _ HTN Insulin resistance _ IFG, IGT, GDM, T2DM Prothrombotic state Proinflammatory state Non-Alcoholic Fatty liver disease Others? The Metabolic Syndrome: A Little History HTN-Hyperglycemia-Gout - Kylin 1923 Insulin Insensitivity - Himsworth 1936 Diabetogenic Obesity - Vague 1947 Syndrome X Reaven 1988 WHO - Metabolic Syndrome 1998 NCEP - Metabolic Syndrome 21 Dysmetabolic Syndrome (277.7) 23 International Consensus 29 Circulation 12: , 29

3 Consensus Definition: The Metabolic Syndrome Diagnosis Established When 3 are Present: Elevated Waist Circumference Men: > 4 in; Women: > 35 in Population and country specific Elevated Triglycerides: 15 mg/dl* Low HDL Cholesterol* Men: < 4 mg/dl Women: < 5 mg/dl Elevated Blood Pressure: 13/85* Elevated Fasting Glucose: 1 mg/dl* Circulation 12: , 29 Population Specific Waist Circumference Thresholds Population Waist Circumference (cm) Men Women Caucasian Asian 9 8 Middle East 94 8 Sub-Saharan African 94 8 Central/South America 9 8 Circulation 12: , 29 Problems With the Definitions Should all factors be given the same weight? Who measures waist circumference? Is Impaired Fasting Glucose even at the 1 mg/dl cutoff sensitive enough? And now should we be using the A1c ( 5.7%)? What about treated risk factors, should they still count?

4 The Metabolic Syndrome: The Pragmatics Easily applied Vital signs blood pressure waist circumference - at least in some clinics Fasting blood work (glucose, lipids) Economical cost of vital signs included in clinic visit FLP/BG ~$3 Easy for patients to understand Broad acceptance ICD-9 code in USA And So Why Should We Care About The Metabolic Syndrome? Abdominal Adiposity as a Component of Cardiometabolic Risk T2DM Elevated Hs-CRP Elevated Elevated TG Blood Pressure Abdominal Adiposity Insulin Resistance Elevated Blood Glucose Low HDL CVD

5 57 Million Reasons Diabetes Prevention Program Progression to Diabetes 4 Cumulative Incidence of Diabetes (%) %/yr Year N Engl J Med 22;346: The Metabolic Syndrome Type 2 Diabetes Incidence 3-fold Kokalainen P et al Diabetes Care, fold Park PJ et al Diabetes Care, 22 2,3-fold Hanson RL et al Diabetes, 22 5,9-fold Laaksonen DE et al Am J Epid, 22 3-fold Lorenzo C et al Diabetes Care, 23 6-fold Nakanishi N et al Diab Res Clin Pract, 24 2,4-fold Wang JJ et al Horm Metab Res, 24 6-fold Wilson PW et al Circulation, 25 2,3-fold Wannamethee SG et al Arch Int Med, 25 2,3-fold Wang JJ et al Atherosclerosis, 26 4-fold Meigs JB et al JCEM, 26 6,7-fold Lorenzo C et al Diabetes Care, 27

6 Association of the Metabolic Syndrome with CHD Prevalence of CHD MS absent MS present Normal Glucose Tolerance Impaired Fasting Glucose Type 2 Diabetes Diabetes Care 24:683, 21 Metabolic Syndrome and Cardiovascular Disease Mortality Middle-Aged Men Median Follow Up 11.6 y Relative Risk CHD CV Disease All-Cause Mortality JAMA 288:279, 22 The Metabolic Syndrome CVD Risk Overall, the approximate risk of CHD in patients with the Metabolic Syndrome is fold higher than those without it. Is the CVD risk of the syndrome greater than the sum of its parts? Does the presence of the Metabolic Syndrome predict CVD incidence better than already established risk assessments?

7 The Metabolic Syndrome Other Associated Conditions Nonalcoholic Fatty Liver Disease OSA PCOS Hypogonadism Lipodystrophies Microvascular Disease Others Is There a Unifying Pathophysiologic Cause of the Metabolic Syndrome? Maybe Maybe Not Abdominal adiposity and Insulin Resistance appear to be at core of pathophysiology of the Metabolic Syndrome AND its individual components The Consequences of the Metabolic Syndrome Obesity Hyperinsulinemia Insulin Resistance Diabetes Dyslipidemia Thrombosis Hypertension Repro-Endo Macrovascular Disease NAFLD

8 Visceral Adiposity, Insulin Resistance and the Metabolic Syndrome Insulin resistance may or may not be unifying pathophysiologic cause of the Metabolic Syndrome Nevertheless, targeting visceral adiposity and insulin resistance should be central to the management of the Metabolic Syndrome patient All of the components of the Metabolic Syndrome improved when adiposity and insulin resistance are targeted Clinical Management of The Metabolic Syndrome Who Should We Screen? If one feature is present look for the others! Screen everyone over age 4 Screen everyone who is obese and/or has elevated waist circumference Look for the pattern

9 The Metabolic Syndrome: Treatment Goals Obesity Hyperinsulinemia Insulin Resistance Diabetes Dyslipidemia Thrombosis Hypertension Repro-Endo Macrovascular Disease NAFLD Weight Loss Interventions: Guide to Selecting Treatment BMI Treatment >4 Diet, Exercise Pharmacology Surgery w/ comorbidities w/ comorbidities + Diabetes Prevention Program Change in Weight (kg) Year Placebo Lifestyle Knowler et al. N Engl J Med 22;346:

10 Diabetes Prevention Program 4 Placebo Cumulative Incidence of Diabetes (%) Lifestyle 58% _ Year N Engl J Med 22;346: Diet: Treating Abdominal Adiposity Hypocaloric diet and weight loss improve insulin sensitivity Unclear what the ideal diet is Inexpensive and effective But will it happen? Physical Activity _ visceral adiposity Improves insulin sensitivity _ Fitness CVD & T2DM Weight Loss Pharmacotherapy Effective Lack of buy in by providers and patients? Cost? Bariatric Surgery The Metabolic Syndrome: Treatment Goals Obesity Hyperinsulinemia Insulin Resistance Diabetes Dyslipidemia Thrombosis Hypertension Repro-Endo NAFLD Macrovascular Disease

11 Treating Insulin Resistance Weight loss Diet Physical Activity Insulin Sensitizers Pharmacotherapy What are the goals? Diabetes Prevention Program Change in Weight (kg) Year Placebo Metformin Lifestyle Knowler et al. N Engl J Med 22;346: Diabetes Prevention Program 4 Placebo Cumulative Incidence of Diabetes (%) Metformin Lifestyle 31% _ 58% _ Year N Engl J Med 22;346:

12 STOP NIDDM: Risk Reduction with Acarbose New Diabetes 24% p=.2 New hypertension 34% p=.6 Myocardial infarction 91% p=.2 Any CV event 49% p=.3 Chiasson JL et al. JAMA 23;29: TRIPOD Study Prevention of Diabetes with TZD Therapy 6 % with Diabetes P=.8 Placebo 56% relative risk reduction Troglitazone Months of Trial 5 6 Diabetes 51: , 22 DREAM Study: The Effects of Rosiglitazone on Diabetes Progression Cumulative hazard rate % RRR HR.4 (.35.46) P <.1 Placebo.2.1 Rosiglitazone No. at risk Placebo Rosiglitazone Follow-up (years) Lancet. 26;368:

13 So What Should We Do? Proposed Clinical Approach Identify At-risk Populations Encourage Lifestyle Changes Weight Loss (~5%) Increased activity Improvement body weight, glucose, lipids, etc No improvement/worsening Lifestyle changes Wt Loss Agents Metformin TZDs The Metabolic Syndrome: Treatment Goals Obesity Hyperinsulinemia Insulin Resistance Diabetes Dyslipidemia Thrombosis Hypertension Repro-Endo NAFLD Macrovascular Disease Treating the Comorbidities Dyslipidiemia Primary goal should be LDL-C lowering Secondary goals should be Non-HDL-C lowering or Tg lowering and/or HDL-C raising Elevated BP: Unclear goals - < 13/8? ACE inhibitors or ARBs should be first line Pro-Thrombotic State: Aspirin

14 The Metabolic Syndrome Summary of the Problem Very common Prevalence is increasing Associated with significant comorbidities HTN Dyslipidemia Repro-Endo issues Atherosclerotic Cardiovascular Disease Progression to T2DM Many unanswered questions

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