Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk

RALPH A. DEFRONZO DEVJIT TRIPATHY PHD DAWN C. SCHWENKE PHD MS MARYANN BANERJI FACP GEORGE A. BRAY THOMAS A. BUCHANAN STEPHEN C. CLEMENT ROBERT R. HENRY T e c h n o l o g i e s OBJECTIVEdIndividuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance. RESEARCH DESIGN AND METHODSdWe studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years. RESULTSdIn a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, G0-120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln I0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [I0-120/ G0-120]) during the OGTT was associated with decreased risk of diabetes. Higher b-cell function (insulin secretion/insulin resistance or disposition index; ln [I0-120/G0-120 3 Matsuda index of insulin sensitivity]; odds ratio 0.11; P , 0.0001) was the variable most closely associated with reduced risk of diabetes. CONCLUSIONSdIn a stepwise multiple-variable analysis, only HbA1c and b-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P , 0.0001). - I erance (IGT) are at high risk for dindividuals with impaired glucose tolabetes; ;50% of all IGT subjects progress to diabetes during their lifetime, with annual diabetes conversion rates that vary between 3 and 11% (1,2). Therefore, it is important to identify these individuals at high risk and to institute preventive therapy, be it lifestyle modification (3,4) or pharmacologic therapy, to prevent the c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c development of microvascular and macrovascular complications (511). In ACT NOW, 602 IGT subjects at high risk were randomly assigned to receive therapy with placebo or pioglitazone, in addition to advice about diet and exercise (7,12). During a mean follow-up period of 2.4 years, subjects in the placebo and pioglitazone groups experienced conversion to diabetes at the rates of 7.6 and 2.1%, respectively (hazard ratio 0.28; P , 0.00001). All subjects in ACT NOW underwent baseline phenotypic, anthropometric, and clinical measurements. An oral glucose tolerance test (OGTT) measuring plasma glucose, free fatty acid (FFA), insulin, and C-peptide (CP) concentrations was performed to provide indices of glucose tolerance, insulin secretion, b-cell function, and insulin sensitivity at baseline (1217). In the current study, we describe those variables that are independent predictors of type 2 diabetes mellitus (T2DM) in IGT subjects treated with placebo in ACT NOW, and we describe a multivariate model that is highly predictive of the eventual development of diabetes. In the predictive model, we used variables that are routinely obtained by practicing physicians, as well as physiologic variables derived from the OGTT. RESEARCH DESIGN AND METHODS Subjects A total of 602 subjects at high risk (fasting plasma glucose [FPG] of 95125 mg/dL and at least one additional risk factor for diabetes) with IGT (2-h plasma glucose 140199 mg/dL) comprised the ACT NOW study population. Additional inclusion and exclusion criteria have been published (7,12). Demographic, anthropometric, and metabolic characteristics of the 602 subjects at baseline were similar in pioglitazone-treated and placebo-treated groups and have been published previously (7). In this study, we report 228 placebo-treated IGT subjects who completed the study and underwent an endof-study OGTT or who experienced conversion to diabetes and underwent an end-of-study OGTT (Table 1). Subjects who were treated with pioglitazone, lost to follow-up, or who dropped out and did not undergo end-of-study OGTT were not included in the present analysis. Study design Detailed descriptions of the study design (12) and results have been published (1). Briefly, eight centers participated in the study, which was approved by each sites Institutional Review Board. After eligibility was determined, 602 IGT subjects were randomized by center or sex to receive pioglitazone or placebo. Subjects were recruited over the course of 2.1 years and followed up for a median of 2.4 years. At baseline, all subjects underwent a 75-g OGTT with plasma glucose, insulin, CP, and FFA concentrations measured at 230, 215, and 0 min and every 15 min for 2 h. Additional baseline assessments included medical history, physical examination, HbA1c, lipid profile, screening blood tests, urinalysis, and electrocardiogram. Plasma glucose, FFA, insulin, CP, HbA1c, and lipids were measured in a central laboratory (Texas Diabetes Institute, San Antonio, TX) (7,12). Body weight (nearest 0.1 kg on digital scale; Health-O-Meter, Bridgeview, IL) and height (nearest 0.1 cm) were recorded. Waist circumference was measured with a Gulick II Tape Measure (Gays Mills, WI) at the midpoint between the highest point at the iliac crest and the lowest part of the costal margin in the midaxillary line. Total body fat and percent body fat were measured by dualenergy X-ray absorptiometry (Hologic 4500; Hologic, Boston, MA). Participants were randomized to pioglitazone 30 mg/day or placebo and returned at 2, 4, 6, 8, 10, and 12 months during the first year and then every 3 months thereafter. Subjects were followedup until they reached the primary end point of diabetes, dropped out, were lost to follow-up, or reached study end. FPG was determined at each follow-up visit. HbA1c was measured every 6 months, and OGTT was performed annually. Baseline Table 1dBaseline characteristics of the 228 placebo-treated IGT subjects who underwent baseline and end-of-study OGTTs Data are mean 6 SD unless otherwise indicated. Placebo (n = 228) measurements were repeated at the end of the study or at the time of conversion to diabetes. IGT conversion to diabetes. The primary outcome was development of diabetes defined as FPG $126 mg/dL or 2-h glucose during OGTT $200 mg/dL. The diagnosis was confirmed by a repeat OGTT (2-h glucose $200 or FPG $126 mg/dL). Data analysis Matsuda index (MI) of insulin sensitivity was calculated from plasma glucose and insulin concentrations during OGTT (18) as follows: MPI and MPG indicate mean plasma insulin and mean plasma glucose concentrations, respectively, during the OGTT. The incremental area under plasma glucose, insulin, CP, and FFA curves during OGTT were determined using the trapezoidal rule. Insulin secretion (...truncated)