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Impact of Insulin Resistance on Risk of Type 2 Diabetes and Cardiovascular Disease in People With Metabolic Syndrome

¹ Harvard Medical School and the General Medicine Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
² The Manchester Diabetes Centre, Manchester Royal Infirmary, Manchester, U.K.
³ Division of Cardiovascular and Endocrine Sciences, School of Medicine, University of Manchester, Manchester, U.K.
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
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
⁶ Department of Mathematics, Statistics, and Consulting Unit, Boston University, Boston, Massachusetts
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{at}partners.org

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 resistance 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 criteria may require insulin resistance to increase risk for CVD. The simultaneous presence of metabolic syndrome and insulin resistance identifies an especially high-risk individual.

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, International Diabetes Federation • IFG, impaired fasting glucose, NCEP, National Cholesterol Education Program • OGTT, oral glucose tolerance test

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