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1.  Actos Now for the prevention of diabetes (ACT NOW) study 
Background
Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.
Methods/Design
602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.
Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.
Conclusion
ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.
Trial Registration
clinical trials.gov identifier: NCT00220961
doi:10.1186/1472-6823-9-17
PMCID: PMC2725044  PMID: 19640291
2.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
OBJECTIVE
Individuals 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 METHODS
We 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.
RESULTS
In 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 β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
CONCLUSIONS
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
doi:10.2337/dc13-0520
PMCID: PMC3816921  PMID: 24062330
3.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
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; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × 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 PGZ-treated 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 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-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 β-cell function was most closely associated with final glucose tolerance status.
doi:10.2337/db13-0265
PMCID: PMC3806596  PMID: 23863810
4.  Effect of intensive treatment of hyperglycemia on microvascular complications of type 2 diabetes in ACCORD: a randomized trial 
Lancet  2010;376(9739):419-430.
Design
ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of <6.0% versus standard therapy with a target of 7.0 to 7.9% reduces cardiovascular disease (CVD) morbidity, mortality, and microvascular complications in participants with type 2 diabetes.
Methods
Volunteers with established type 2 diabetes, HbA1c levels ≥ 7.5% and CVD or two or more CVD risk factors were recruited at 77 clinical sites across the U.S. and Canada. Instructional materials, behavioral counseling, glucose-lowering medications and self-monitoring supplies were provided by the study. Therapeutic regimens were individualized on the basis of randomized assignment and response to therapy. This investigation examines the effect of treatment to glycemic goals on occurrence of microvascular diabetes complications. Prespecified composite outcomes were: 1) dialysis or renal transplantation, or serum creatinine >291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment.
Results
A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p<0.05) included development of macroalbuminuria, cataract extraction, visual acuity, a score of >2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch.
Conclusions
Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.
doi:10.1016/S0140-6736(10)60576-4
PMCID: PMC4123233  PMID: 20594588
5.  Diabetic Retinopathy, Its Progression, and Incident Cardiovascular Events in the ACCORD Trial 
Diabetes Care  2013;36(5):1266-1271.
OBJECTIVE
Both the presence of diabetic retinopathy and its severity are significantly associated with future cardiovascular (CV) events. Whether its progression is also linked to incident CV outcomes hasn’t been assessed.
RESEARCH DESIGN AND METHODS
The relationship between retinopathy, its 4-year progression, and CV outcomes (CV death or nonfatal myocardial infarction or stroke) was analyzed in participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who also participated in the ACCORD Eye Study. Retinopathy was classified as either none, mild, moderate, or severe, and worsening was classified as a <2-step, 2–3-step, or >3-step change (that included incident laser therapy or vitrectomy).
RESULTS
Participants (n = 3,433) of mean age 61 years had baseline retinal photographs (seven stereoscopic fields). Compared with no retinopathy, the adjusted HRs (95% CI) for the CV outcome rose from 1.49 (1.12–1.97) for mild retinopathy to 2.35 (1.47–3.76) for severe retinopathy. A subset of 2,856 was evaluated for progression of diabetic retinopathy at 4 years. The hazard of the primary outcome increased by 38% (1.38 [1.10–1.74]) for every category of change in retinopathy severity. Additional adjustment for the baseline and follow-up levels of A1C, systolic blood pressure, and lipids either individually or together rendered the relationships between worsening and CV outcomes nonsignificant.
CONCLUSIONS
Both the severity of retinopathy and its progression are determinants of incident CV outcomes. The retina may provide an anatomical index of the effect of metabolic and hemodynamic factors on future CV outcomes.
doi:10.2337/dc12-1311
PMCID: PMC3631868  PMID: 23238658
6.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
Objective
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Conclusions
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
doi:10.1161/ATVBAHA.112.300346
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone

Results 1-6 (6)