Impact of Insulin Resistance on Risk of Type 2 Diabetes and Cardiovascular Disease in People With Metabolic Syndrome JAMES B. MEIGS, MD, MPH 1 MARTIN K. RUTTER, MD 2,3 LISA M. SULLIVAN, PHD 4 CAROLINE S. FOX, MD, MPH 5 RALPH B. D’AGOSTINO,SR., PHD 6 PETER W.F. WILSON, MD 7 OBJECTIVE — Metabolic syndrome increases the risk for type 2 diabetes and cardiovascular disease (CVD) and may be associated with insulin resistance. RESEARCH DESIGN AND METHODS — We tested the hypothesis that the metabolic syndrome confers risk with or without concomitant insulin resistance among 2,803 Framingham Offspring Study subjects followed up to 11 years for new diabetes (135 cases) or CVD (240 cases). We classified subjects by presence of metabolic syndrome (using the National Cholesterol Education Program’s [NCEPs] Third Adult Treatment Panel [ATP III], International Diabetes Federation [IDF], or European Group for the Study of Insulin Resistance [EGIR] criteria) and insulin resistance (homeostasis model assessment of insulin resistance 75th percentile) and used separate risk factor–adjusted proportional hazards models to estimate relative risks (RRs) for diabetes or CVD using as referents those without insulin resistance, metabolic syndrome, or without both. RESULTS — Fifty-six percent of individuals with ATP III, 52% with IDF, and 100% with EGIR definitions of metabolic syndrome had insulin resistance. Insulin resistance increased risk for diabetes (RR 2.6 [95% CI 1.7– 4.0]) and CVD (1.8 [1.4 –2.3]) as did metabolic syndrome for diabetes (ATP III, 3.5 [2.2–5.6]; IDF, 4.6 [2.7–7.7]; and EGIR, 3.3 [2.1–5.1]) and CVD (ATP III, 1.8 [1.4 –2.3]; IDF, 1.7 [1.3–2.3]; and EGIR, 2.1 [1.6 –2.7]). Relative to those without either metabolic syndrome or insulin resistance, metabolic syndrome and insulin resistance increased risk for diabetes (ATP III, 6.0 [3.3–10.8] and IDF, 6.9 [3.7–13.0]) and CVD (ATP III, 2.3 [1.7–3.1] and IDF, 2.2 [1.6 –3.0]). Any instance of metabolic syndrome without insulin resis- tance increased risk for diabetes approximately threefold (P  0.001); IDF metabolic syndrome without insulin resistance (RR 1.6, P = 0.01), but not ATP III metabolic syndrome without insulin resistance (RR 1.3, P = 0.2), increased risk for CVD. CONCLUSIONS — Metabolic syndrome increased risk for diabetes regardless of insulin resistance. Metabolic syndrome by ATP III cri- teria may require insulin resistance to increase risk for CVD. The simultaneous presence of metabolic syndrome and insulin resistance identifies an especially high-risk individual. Diabetes Care 30:1219 –1225, 2007 P eople with the cluster of risk factors including obesity, impaired fasting glucose (IFG), hypertension, low HDL cholesterol, and elevated triglycer- ides are thought to have the “metabolic syndrome,” reflecting underlying insulin resistance. Both the metabolic syndrome and insulin resistance are factors in the development of type 2 diabetes and car- diovascular disease (CVD) (1). Several competing definitions of metabolic syn- drome are in use, and each is differently linked to the presence of insulin resis- tance. These definitions include that of the National Cholesterol Education Pro- gram (NCEP) Third Adult Treatment Panel (ATP III) (2), the International Dia- betes Federation (IDF) (3), and the Euro- pean Group for the Study of Insulin Resistance (EGIR) (4). The EGIR defini- tion requires the presence of insulin resis- tance plus any two other metabolic traits; ATP III and IDF definitions require at least three metabolic traits but do not re- quire the presence of insulin resistance. In studies of ATP III metabolic syndrome, as many as half of subjects do not have insu- lin resistance (5–7). There are few population-based data comparing how well the ATP III or IDF metabolic syndrome definitions identify subjects with insulin resistance (8) or comparing how well ATP III, IDF, or EGIR metabolic syndrome definitions predict subsequent risk for incident dia- betes (9,10) or CVD (11–13). In addition, while it has been implied that the pres- ence of the metabolic syndrome is a sur- rogate for the presence of insulin resistance, there are few data on diabetes or CVD risk associated with metabolic syndrome in the absence of insulin resis- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Harvard Medical School and the General Medicine Division, Department of Medicine, Massachu- setts General Hospital, Boston, Massachusetts 2 The Manchester Diabetes Centre, Manchester Royal Infir- mary, Manchester, U.K.; the 3 Division of Cardiovascular and Endocrine Sciences, School of Medicine, University of Manchester, Manchester, U.K.; the 4 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts ; the 5 Division of Endocrinology, Metabolism, and Diabetes, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, and the National Heart, Lung, and Blood Institute’s Framingham (Mass) Heart Study; the 6 Department of Mathematics, Statistics, and Consulting Unit, Boston University, Boston, Massachusetts; and the 7 Emory University School of Medicine, Atlanta, Georgia. Address correspondence and reprint requests to James B. Meigs, MD, MPH, General Medicine Division, Massachusetts General Hospital, 50 Staniford St., 9th Floor, Boston, MA 02114. E-mail: jmeigs@ partners.org. Received for publication 7 December 2006 and accepted in revised form 18 January 2007. Published ahead of print at http://care.diabetesjournals.org on 26 January 2007. DOI: 10.2337/dc06- 2484. J.B.M. currently has research grants from GlaxoSmithKline, Wyeth, and sanofi-aventis and serves on safety or advisory boards for GlaxoSmithKline, Merck, and Eli Lilly. P.W.F.W. is supported by grants from GlaxoSmithKline and Wyeth. Abbreviations: AROC, area under the receiver operating characteristic curve; ATP III, Third Adult Treatment Panel; CVD, cardiovascular disease; EGIR, European Group for the Study of Insulin Resistance; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; IDF, Interna- tional Diabetes Federation; IFG, impaired fasting glucose, NCEP, National Cholesterol Education Program; OGTT, oral glucose tolerance test. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Cardiovascular and Metabolic Risk O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 30, NUMBER 5, MAY 2007 1219