The Metabolic Syndrome Gil C. Grimes, MD September 2006

Objectives Define Metabolic Syndrome Review the prevalence in our population Discuss the proposed pathophysiology Review associated morbidity and mortality Define treatment strategies Define the metabolic syndrome. Review the prevalence in our population. Discuss the proposed pathophysiology. Define treatment strategies and paradigms

Definitions

World Health Organization Definition One of these Insulin resistance Impaired glucose regulation FPG ≥ 110 mg/dl and/or 2 hour PG ≥ 140 mg/dl Two of these Hypertension SBP ≥ 140 DBP ≥ 90 Elevated Triglycerides (≥ 150 mg/dl) and/or low HDL (≤35 mg/dl males and ≤39 mg/dl females) Central Obesity waist to hip ratio >0.90 males, >0.85 females, or BMI>33 kg/m2 Microalbuminuria urinary albumin excretion rate ≥ 20 mg/min or albumin/creatinine ratio ≥ 30 mg/g Insulin resistance is defined originally as by the use of an insulin clamp In many studies surrogate markers of insulin resistance are utilized Fasting insulin levels Insulin after a 75 gm glucose challenge Albert KGMM et al Diabetic Med 1998;15:539-553 [Level 5]

National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) Definition Three of the following Abdominal circumference Men > 40 inches Women >35 inches Triglycerides > 150 mg/dl HDL Cholesterol Men < 40 mg/dl Women <50 mg/dl Blood Pressure > 130/85 mm Hg Glycemia >110mg/dl Abdomen measurements at umbilicus Correlates better than BMI Expert panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:2486-2497 [Level 5]

Prevalence This is from the New York Time September 2003 A new food item deep fried with the taste of a cheeseburger and fries all in one Decline in the amount of exercise Segway may make things worse Look at the people in these photos How many can you identify that are at risk for metabolic syndrome

Obesity US 1991 Data from the behavior risk factor surveillance survey Telephone survey people >18 who were non-institutionalized [Level 2b]

Obesity US 1992 [Level 2b]

Obesity US 1993 [Level 2b]

Obesity US 1994 [Level 2b]

Obesity US 1995 [Level 2b]

Obesity US 1996 [Level 2b]

Obesity US 1997 [Level 2b]

Obesity US 1998 [Level 2b]

Obesity US 1999 [Level 2b]

Obesity US 2000 [Level 2b]

Obesity US 2001 [Level 2b]

Texas 2001 Texas subset from the Behavioral Risk Factor Surveillance System Look closely at the number of those obese White 60% Black 75% Hispanic 70% Multiracial 55% Other 46% Behavioral Risk Factor Surveillance System, 2001 CDC [Level 2b]

Prevalence in FOS and SAHS populations Frammingham offspring study Prospective community study Looked at 3,224 patients Virtually all white 85% of those eligible participated 1991-1995 data San Antonio Heart Study Prospective community based study Data from the survivors (73.7%) 1988 to 1996 data Looked at a total of 1081 Non-hispanic Looked at a total of 1656 hispanic Range is up to 33% Note the increased number of Mexican Americans with metabolic syndromes Meigs J et al Diabetes 2003; 52:2160-7 [Level 2c]

Prevalence Metabolic Syndrome in NHANES III Metabolic Syndrome increases with age Based on NHANES II data 1988-1994 data set Ford ES et al JAMA 2002;287:356-359 [Level 2 c]

Prevalence Metabolic Syndrome in NHANES III by Race Note the over-representation of hispanics Ford ES et al JAMA 2002;287:356-359 [Level 2 c]

Prevalence in Adolescents from NHANES III 5 percent prevalence rate for Metabolic syndrome Data from 1988-1994 Cook S et al Arch Pediatric Adolec Med 2003;157:821-827 [Level 2c]

Pathophysiology

Proposed Pathophysiology Role of adipose tissue and inflammation IL-6 (pro-inflammatory compound) Produces 25% of IL-6 Stimulate acute phase hepatic protein production Obesity associated with increased C-reactive protein Represents chronic low level inflammation More related to Waist to hip ratio than BMI This is speculative. Based on blood samples from NHANES III The black bars are raised CRP levels in this group Increased with increased BMI especially in females There are several lines of evidence that inflammation plays an integral role in the syndrome Unclear on whether it is a chicken egg thing Does metabolic syndrome predispose you to low level inflammation? Doe low level inflammation lead to metabolic syndrome? Is is adipose poisoning? Visser M et al JAMA 1999;282:2131-2135 [Level 2b]

CRP and BMI Visser M et al JAMA 1999;282:2131-2135 [Level 2b] NHANES III data Closer look at BMI vs Waist Hip in women BMI correlates better for Women than Waist Hip Ratio for increased CRP Women faired worse than men Both groups showed increase with obesity Change remained significant after adjustment for comorbid conditions Visser M et al JAMA 1999;282:2131-2135 [Level 2b]

CRP, IL-6, and subsequent DM Data from Women’s Health Study Looked at women who subsequently developed DM and examined Il-6 and CRP 27,628 total patients Of those 180 developed Diabetes within the trial period Matched to 362 case control that did not develop diabetes Looking at two different BMI (darker heavier) Comparing relative risk of developing diabetes with the Il-6 or CRP level Higher baseline predictive even with normal BMI Pradhan AD et al JAMA 2001;286:327-334 [Level 2b]

Cartoon of mechanism of disease

Associated Morbidity and Mortality

CHD Morbidity and Mortality This is from the Kuopio Ischaemic Heart Diease Risk Factor Study Population based cohort study of 1209 finish men 42-60 years of age 1984-1989 inception Follow up through 1998 There is an increased risk of death as a direct result of MI, or as a result of CVD (Heart failure etc). There is also and increased risk of all cause mortality although not as drastic. Lakka H et al JAMA 2002; 288:2709-2016 [Level 1b]

Metabolic Syndrome as a Risk for CHD and Diabetes West of Scotland Coronary Prevention Study 5974 men Followed 4.9 years Metabolic syndrome conveyed the same risk as smoking or increasing your age by 10 years for CHD Dramatic increase in risk for DM Sattar N et al Circulation 2003:108:414-9 [Level 2b]

Risks for CHD and CVA Morbidity Botnia Study Group Examined families goal of identifying early defects in families with DM-2 Examined 4,483 subjects Looked at the development of Coronary Heart Disease or Cerebral Vascular Disease Presence of Metabolic syndrome conferred increased risk of both Isomaa B et al Diabetes Care 2001;24:683-689 [Level 2b]

Risk for CHD Mortality Finish Study group Botnia 3.606 subjects 10% died 5.8% from CHD Of those who died metabolic syndrome increased risk of death and of CHD mortality compared with no metabolic syndrome Isomaa B et al Diabetes Care 2001;24:683-689 [Level 1a]

Risk for CHD and Diabetes From the West Scotland Study Sattar N et al Circulation 2003:108:414-9 [Level 2b]

Risk for DM from Kuopio IHD Risk Factor Study Presence of Metabolic Syndrome Odds Ratio of developing DM 10 4 fold increased risk for DM WHO Definition with Waist Hip Ratio >0.90 Sensitivity 0.83 Specificity 0.78 NCEP Definition Sensitivity 0.57 Specificity 0.90 Finish study of 1004 men followed for four years This is from the Kuopio Ischaemic Heart Diease Risk Factor Study Population based cohort study of 1209 finish men 42-60 years of age 1984-1989 inception Follow up through 1998 Laaksonen D et al Am J Epidemiol 2002;156:1070-1077 [Level 2b]

Treatment

Treatment Prevention is the Key Diminish the adipose poisoning Must extrapolate from other studies Diabetes Prevention Program Goal 150 minutes of exercise weekly Low fat diet Nutrition counseling every 90 days NNT 8 people for 3 years to prevent 1 new DM Absolute Risk Reduction 12.77% Finish Study over six years mean follow up 3.2 years Recruited high risk individuals (first degree relative with DM), obese patients, those with impaired fasting glucose 172 men 350 women Randomly assigned to intense intervention vs control Confidence interval 5.2 to 15.5 Tuomilheto J et al NEJM 2001;344:1343-1350 [Level 1a]

Treatment Lifestyle vs. Metformin Similar design NNT for 3 years to prevent on case of DM Lifestyle 6.9 Metformin 13.9 Diabetes Prevention Group Random Assignment 3234 non-diabetic with increased fasting or post load glucose concentrations Lifestyle group 150 minutes physical activity weekly vs metformin 850 mg BID Diabetes Prevention Program Group NEJM 2002;346:393-403 [Level 1a]

Treatment Lifestyle vs. Xenical Subgroup analysis of Xenical trial 40% of patients positive for Metabolic syndrome Type II DM 13.9% lifestyle group Type II DM 9.8% Xenical group Industry sponsored study Never published outside of this presentation. Torgerson J et al 12th European Congress on Obesity 2003 [Level 2b ?]

Statins et al Presence of Metabolic Syndrome indicates at least 2 risk factors LDL goal <100 mg/dl Statins reduce LDL on average 18-55% Fenofibrate reduce Triglycerides 20-50% and raise HDL 10-35% Niacin reduce LDL 5-25% Triglycerides 20-50% and raise HDL 15-35% Combinations work well, caution for increased risk of adverse events O‘Mara NB Prescriber’s Letter 2003;19:191001

Control the Pressure JNC 7 guidelines and ALLHAT tell us to lower the pressure Intensive lifestyle modification HOPE trial 32% reduction in new onset DM for ramipril LIFE trial Losartan 6% developed DM Atenolol 8% developed DM It appears form recent evidence that it takes High Dose Ramipril to achieve this change There is an underlying question as to whether Beta Blockers may not be as good as ACE/ARB in Prevention of DM

Aspirin Therapy Routine recommendation for those at increased risk for cardiovascular disease Unclear if it decreases progression of Metabolic Syndrome Use based on High Risk status of these patients

Sample Patient 38 year old male Weight 250 lbs Height 72 inches BMI 34 BP 140/86 Screen Glucose? Screen Lipids? Therapy?

Take Home It is common in our patients The prevalence is expected to increase The process starts early The intervention needs to start early Get your patients up and moving