What is the Etiology(ies) of the Metabolic Syndrome?NIDDK Diabetes Mellitus Interagency Coordinating Committee (DMICC)The Metabolic SyndromeNIH Campus, Bethesda, MDFebruary 25, 2003 Steven M. Haffner, MD Professor University of Texas Health Science Center at San Antonio San Antonio, Texas
Criteria for Comparing Different Definitions for Metabolic Syndrome • Risk of • CHD • DM • Relation to insulin resistance • Prevalence in community could differ by race NCEP: 2 lipid criteria WHO: 1 lipid criteria African Americans have low triglycerides and high HDL and thus a lower prevalence of MS by NCEP than WHO 4. How simple is the definition?
Outline • Methodological issues • Prediabetic State • Factor analyses (role of HBP) • Insulin as a predictor of MS, and CHD • Subclinical inflammation and MS • Do BP/lipid therapies work in MS?
Data Sets • San Antonio Heart Study • NHANES • Insulin Resistance Atherosclerosis Study • Direct measure of IR • Three ethnic groups • Framingham Study (Factor Analyses) • Mexico City Diabetes Study
Etiology of Metabolic Syndrome • Insulin Resistance (IRS) • Syndrome X: Reaven, Diabetes 1987 • IRS: Ferrannini, Diabetologia 1991 • IRS: Haffner, Diabetes 1992 2. Obesity • Visceral fat: Despres (many papers)(“hypertriglyceridemic waist”) • Weight gain: Peter Wilson, Arch Int Med, 2000
Etiology of Metabolic Syndrome (continued) • Glycemia: non diabetic range • Gerstein: Dysglycaemic Syndrome • DECODE data: Post-prandial (“actually post glucose load”) glycemia and CVD • Cardiovascular risk factors (no additional effect of MS) • Subclinical Inflammation
The Prediabetic State • Early attempt at the metabolic syndome (IRS) • Glucose vs insulin as cause of elevated CVD risk
80 60 40 20 0 MI and Microvascular End Points: Incidenceby Mean Systolic BP and HbA1c Concentration 50 MI Microvascular end points MI Microvascular end points 40 30 Adjusted incidence/1000 person-y (%) Adjusted incidence/1000 person-y (%) 20 10 0 110 120 130 140 150 160 170 5 6 7 8 9 10 11 Updated mean systolic BP (mm Hg) Updated mean HbA1cconcentration (%) Adler et al. BMJ. 2000;321:412. Stratton et al. BMJ. 2000;321:405.
Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes Relative Risk Nondiabetic throughout the study Prior to diagnosis of diabetes After diagnosis of diabetes Diabetic at baseline Hu FB, et al. Diabetes Care 2002;25(7):1129-1134.
Age- and Sex-Adjusted Anthopometric Variables and Cardiovascular Risk Factors at Baseline (Mean) in Subjects with Normal Glucose Tolerance at Baseline According to Conversation Status at 8-Year Follow-Up
Conversion to Type 2 Diabetes (7-Year Incidence) Low Insulin Secretion Low Low Neither Low High Insulin-Resistant High High Metabolic Status HOMA IR Δ I30-0min/Δ G30-0min Both High Low Haffner et al. Circulation 2000; 101: 975-980.
Distribution by Metabolic Status Among Converters to Type 2 Diabetes Low insulin secretion; insulin sensitive (15.9%) Neither (1.5%) Both (54%) Insulin resistant; good insulin secretion (28.7%) (n=195) Haffner et al. Circulation 2000;101:975–980.
Mean Triglyceride Levels by Insulin Resistance/Secretion Category P<0.0001 P=0.033 P=0.47 220 200 180 160 Triglyceride (mg/dL) 140 120 100 Converters to type 2 diabetes Non-converters (all) Metabolic status HOMA IR DI30–0 min/DG30–0min Low insulin secretion low low Insulin-resistant high high Haffner et al. Circulation 2000;101:975–980.
Mean HDL Cholesterol by Insulin Resistance/Secretion Category P<0.0001 P=0.0001 P=0.90 50 40 HDL cholesterol (mg/dL) 30 20 Converters to type 2 diabetes Non-converters (all) Metabolic status HOMA IR DI30–0 min/DG30–0min Insulin-resistant high high Low insulin secretion low low Haffner et al. Circulation 2000;101:975–980.
Mean Systolic Blood Pressure by Insulin Resistance/Secretion Category P<0.0001 130 P=0.035 P=0.66 125 SBP (mm Hg) 120 115 110 Converters to type 2 diabetes Non-converters (all) Insulin-resistant high high Metabolic status HOMA IR DI30–0 min/DG30–0min Low insulin secretion low low Haffner et al. Circulation 2000;101:975–980.
Relationship of Fasting Insulin Levels to Relative Risk for Multiple Metabolic Disorders Baseline insulin Low High Relative Disorder (%) (%) risk P value Hypertension 5.5 11.4 2.04 .020 Hypertriglyceridemia 2.6 8.9 3.46 <.001 Low HDL-C 16.2 26.3 1.63 .012 High LDL-C 16.4 20.1 1.23 .223 Type 2 diabetes 2.2 12.2 5.62 <.001 Haffner SM et al. Diabetes 1992;41:715–722.
Risk of Major CHD Event Associated With High Insulin Levels in Nondiabetic Men Kaplan-Meier Survival Curve 1.00 0.95 Q1 0.90 Proportion without major CHD event 0.85 Q2 Log rank: Overall P=.001 Q5 vs Q1 P<.001 0.80 Q3 Q4 0.75 Q5 0 0 5 10 15 20 25 Years Q1 to Q5=quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile). Pyörälä M et al. Circulation 1998;98:398–404.
Markers of Inflammation and Cardiovascular DiseaseApplication to Clinical and Public Health PracticeA Statement for Healthcare Professionals from the CDC and the AHA Relative Risk Category and Average hs-CRP Level Low: <1 mg/L Average: 1.0 to 3.0 mg/L High: >3.0 mg/L (Class IIa, Level of Evidence B) Pearson T, et al. Circulation 2003; 107:499-511
Partial Spearman Correlation Analysis of Inflammation Markers With Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: IRAS *P<0.05, †P<0.005, ‡P<0.0001 CRP=C-reactive protein; IRS=insulin resistance system; WBC=white blood cell count. Adapted from Festa et al. Circulation 2000;102:42–47.
Mean values of CRP by number of metabolic disorders (dyslipidemia, upper body adiposity, insulin resistance, hypertension): IRAS Festa et al. Circulation 102:42-7, 2000.
Five Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: IRAS % P=0.001 P=0.001 P=0.06 Festa A et al. Diabetes, in press.
Effect of Insulin Sensitizing Interventions on Reducing CRP Levels • Lifestyle DPP – presented AHA, 2002 • Pharmacological • Metformin – presented AHA, 2002 • TZD-Rosiglitazone - Circulation 2002
The Effect of Rosiglitazone on CRP n=124 n=95 n=134 Placebo Rosiglitazone 4 mg/day Rosiglitazone 8 mg/day Difference = -26.8%(95% CI: -39.7, -21.8 ) Difference = -21.8 (95% CI: -34.7, -5.6) Haffner SM et al. Circulation, 2002; 106:679-684
Do Elevated Levels of C-Reactive Protein Predict the Development of the NCEP Metabolic Syndrome? Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean MEJ, Haffner SM. Prospective study of c-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care, 25:2016-2021, 2002.
CRP Predicts a Development of the Metabolic Syndrome (NCEP) in Women but not in Men: Mexico City (Han et al, Diabetes Care, 25:2016-2021, 2002)
Both CRP and BMI Predict a Development of the Metabolic Syndrome (NCEP) in Women: Mexico City Diabetes Study (Han et al, Diabetes Care, 25:2016-2021, 2002)
CRP Predicts Development of the Metabolic Syndrome (NCEP) in Women Independently of BMI and HOMA IR : Mexico City Diabetes Study (Han et al, Diabetes Care, 25:2016-2021, 2002) Additionally adjusting for: - BMI HOMA-IR BMI & HOMA IR 1/2 1 2 4 8 16 Odds ratio (95% CI) for 3rd vs. 1st CRP tertile
Factor Analyses • Framingham Study Meigs, Diabetes 1997 • IRAS Hanley, Diabetes 2002 Conclusion: Hypertension not associated (separate factor) with Insulin Resistance
HTN IGT BP Systolic Fasting Glucose TG Fasting Insulin Body Mass Index BP Diastolic 2-hour Glucose HDL-C Waist- Hip Ratio Central Syndrome 5-6 Traits May Represent 2-4 Physiologic PhenotypesInsulin Resistance Syndrome Factor Pattern Interpretation Meigs et al. Diabetes 1997;46:1594-1600
Factor Analysis of Metabolic Syndrome Using Directly-Measured Insulin Sensitivity: IRAS Loadings > 0.40 in Red; Hanley et al. Diabetes, 2002; 51: 2642-2647.
Summary • Most subjects with the Metabolic Syndrome do not have type 2 diabetes. • The Metabolic Syndrome is associated with increased risk of heart disease although the increased risk may not be entirely due to increased insulin resistance.