Prevention of Diabetes With Pioglitazone in ACT NOW: Physiologic Correlates

Ralph A. DeFronzo Devjit Tripathy Dawn C. Schwenke MaryAnn Banerji George A. Bray Thomas A. Buchanan Stephen C. Clement Amalia Gastaldelli Robert R. Henry Abbas E. Kitabchi Sunder Mudaliar Robert E. Ratner Frankie B. Stentz Nicolas Musi Peter D. Reaven for the ACT NOW Study We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/ insulin resistance (IR; DI0-120 /DG0-120, DIS rate [ISR]0-120 /DG0-120), and b-cell function (DI /DG 3 MI and DISR /DG 3 MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15-0.49]; P , 0.0001); 48% of PGZtreated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P , 0.005). Higher final glucose tolerance status (NGT . IGT . T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.540.80]), IS (OR 0.61 [95% CI 0.50-0.75]), and b-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19-0.37]; all P , 0.0001). Of the factors measured, improved b-cell function was most closely associated with final glucose tolerance status. Diabetes 62:3920-3926, 2013 - with annual diabetes conversion rates ranging from 3 to 11% per year (3). Individuals with IGT have moderate-tosevere insulin resistance (IR) in muscle and impaired second-phase insulin secretion (IS), while those with IFG are characterized by hepatic IR and impaired first-phase IS with intact second-phase IS and normal/near-normal muscle insulin sensitivity (47). IGT conversion to T2DM is associated with a further and progressive decline in b-cell function with little worsening of IR, which is near maximally established in IGT (4,5,810). Treatment with thiazolidinediones improves IS (11) and IR (1215), ameliorates lipotoxicity (12,14), and redistributes fat from muscle/liver/ b-cells to subcutaneous fat depots (12,16). Therefore, they represent a logical choice for the treatment of IGT and IFG. In the ACT NOW Study (17,18), over a 2.4-year period, the annual conversion rate of IGT to T2DM was 7.6% in placebo-treated vs. 2.1% in pioglitazone (PGZ)-treated subjects (hazard ratio 0.28, P , 0.0001) (18). PGZ is a potent insulin-sensitizing agent in muscle, liver, and adipocytes (reviewed in 1214); augments IS; and preserves b-cell function (11,19). These effects are mediated, in part, via peroxisome proliferatoractivated receptor-g (PPAR-g) receptor (13,20) and via reversal of lipotoxicity (12,14) and changes in adipocytokines (20). PGZ reduces plasma free fatty acid (FFA) levels, mobilizes fat out of muscle (21) and liver (22), and redistributes fat from visceral to subcutaneous depots (12,16). In the current study, we examined which physiologic/ metabolic/anthropometric changes (end-of-study versus baseline) in the ACT NOW Study (18) were associated with IGT progression to diabetes and reversion to normal glucose tolerance (NGT) in PGZ- and placebo-treated subjects. RESEARCH DESIGN AND METHODS Subjects. A total of 602 high-risk IGT subjects comprised the study population (17,18). Demographic, anthropometric, and metabolic characteristics at baseline were similar in PGZ and placebo groups (Supplementary Table 1) and have been published (18). Here, we report on 441 subjects who completed the study (Supplementary Table 2). Subjects lost to follow-up or who dropped out and did not undergo end-of-study oral glucose tolerance tests (OGTTs) were not included. During screening, 120 subjects had undergone OGTTs but were not included in the ACT NOW Study because OGTT results were normal. These NGT subjects are included as the control group. Study design. Descriptions of the study design (17) and results have been published (18). Eight centers participated in the study, which was approved by the institutional review board for each site. A total of 602 IGT subjects were randomized to receive PGZ or placebo and were observed for a median time of 2.4 years. At baseline, subjects underwent 2-h 75-g OGTTs with plasma glucose (PG), insulin, C-peptide, and FFA concentrations measured at 230, 215, 0, and every 15 min in Central Laboratory (Texas Diabetes Institute) (17,18). Additional baseline assessments included the following: medical history, physical examination, body mass index (BMI), waist circumference, HbA1c level, lipid profile, screening blood tests, urinalysis, and electrocardiogram. Body fat was measured by dual-energy X-ray absorptiometry (model 4500; Hologic, Bedford, MA). Participants were randomized to receive PGZ, 30 mg, or placebo. After 1 month, the PGZ dose was increased to 45 mg. Participants returned at 2, 4, 6, 8, 10, and 12 months during year 1, and every 3 months thereafter. Subjects were observed until they reached the primary end point of diabetes, dropped out, were lost to follow-up, or reached study end (2 years after the last subject was enrolled). The fasting PG (FPG) level was determined on each visit. HbA1c was measured every 6 months. An OGTT was performed annually. Baseline measurements were repeated at study end or the time of conversion to diabetes. IGT conversion to diabetes. The primary outcome was the development of diabetes (FPG $126 mg/dL or 2-h glucose $ 200 mg/dL). Diagnosis was confirmed by OGTT (2-h glucose $200 mg/dL or FPG $126 mg/dL). Data analysis. The Matsuda index (MI) of insulin sensitivity was calculated from PG and insulin levels obtained during the OGTT (23). The incremental areas under the curves (AUCs) of PG, insulin, C-peptide, and FFA during OGTTs were determined using the trapezoidal rule. The IS rate (ISR) was calculated from deconvolution of plasma C-peptide using standard C-peptide clearances (24). b-Cell function was calculated as the IS/IR (disposition) index (DI0120/DG0120 3 MI; DISR0120/DG0120 3 MI) (47). Adipocyte IR index was calculated as fasting plasma insulin 3 fasting FFA concentration (25). Statistical analyses addressed the following question: what metabolic/ physiologic/anthropometric changes were associated with protection from diabetes in IGT subjects treated with PGZ. Intention-to-treat analyses were conducted using all follow-up data. Continuous variables were compared between treatment groups or subgroups by t tests if normally distributed. Otherwise, nonparametric tests were used. Baseline insulin concentration, insulin AUC, MI of insulin sensitivity, adipose tissue IR index, and IS/IR index were ln transformed before comparisons. Changes from baseline to follow-up were compared bet (...truncated)