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1.  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
2.  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

Results 1-2 (2)