Lincoff, A. M., Wolski, K., Nicholls, S. J. & Nissen, S. E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298, 1180-1188

Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 10/2007; 298(10):1180-8. DOI: 10.1001/jama.298.10.1180
Source: PubMed

ABSTRACT Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes.
To systematically evaluate the effect of pioglitazone on ischemic cardiovascular events.
A database containing individual patient-level time-to-event data collected during pioglitazone clinical trials was transferred from the drug's manufacturer for independent analysis. Trials were included if they were randomized, double-blinded, and controlled with placebo or active comparator.
The primary outcome was a composite of death, myocardial infarction, or stroke. Secondary outcome measures included the incidence of serious heart failure. A fixed-effects approach was used to combine the estimates across the duration strata and statistical heterogeneity across all the trials was tested with the I2 statistic.
A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005). Progressive separation of time-to-event curves became apparent after approximately 1 year of therapy. Individual components of the primary end point were all reduced by a similar magnitude with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (HR, 1.41; 95% CI, 1.14-1.76; P = .002). The magnitude and direction of the favorable effect of pioglitazone on ischemic events and unfavorable effect on heart failure was homogeneous across trials of different durations, for different comparators, and for patients with or without established vascular disease. There was no evidence of heterogeneity across the trials for either end point (I2 = 0%; P = .87 for the composite end point and I2 = 0%; P = .97 for heart failure).
Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.

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Available from: Kathy Wolski, Mar 14, 2014
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    • "After the storm of controversy and bad press, it is unlikely this rosiglitazone will ever be widely used again, as there is no unique benefit for this drug compared to pioglitazone—except perhaps for bladder cancer risk (see below). Furthermore, a similar meta-analysis for pioglitazone showed no excess cardiovascular mortality, and in fact an 18% decrease in cardiovascular endpoints (Lincoff et al., 2007). An large observational cohort of U.S. Medicare patients showed that rosiglitazone has cardiovascular harm compared to pioglitazone (Graham et al., 2010), while a UK cohort study showed that pioglitazone but not rosiglitazone reduced all-cause "
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    ABSTRACT: Type 2 diabetes is caused by insulin resistance coupled with an inability to produce enough insulin to control blood glucose, and thiazolidinediones (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events. Here we review the clinical data and attempt to balance the benefits and risks of TZD therapy. We also examine potential mechanisms of action for the beneficial and harmful effects of TZDs, mainly via agonism of the nuclear receptor PPARγ. Based on critical appraisal of both preclinical and clinical studies, we discuss the prospect of harnessing the insulin sensitizing effects of PPARγ for more effective, safe, and potentially personalized treatments of type 2 diabetes.
    Cell Metabolism 09/2014; 20(4). DOI:10.1016/j.cmet.2014.08.005 · 16.75 Impact Factor
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    • "The absolute bioavailability ranged between 70%-96% with a mean value of 83%. Food slightly delays the time to peak serum concentration 3-4 h, but does not alter the extent of absorption [17] [18] . PTZ is highly bound to plasma proteins (>99%) mainly to serum albumin. "
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    ABSTRACT: Objective: To assess the in vitro-in vivo correlation of immediate release formulation of pioglitazone 30 mg film coated tablet. Methods: In vitro release data were obtained for test and reference formulation using the USP paddle method (Apparatus 2) at 50 r/min and with the temperature of 37 °C in the dissolution meddium of 0.1 mol/L of hydrochloric acid of pH 1.2. Twelve healthy volunteers were administered both test and reference pioglitazone 30 mg tablet orally and blood samples were collected over 24 h period. In-vitro drug concentration were analyzed by a simple, fast and precise reverse phase binary HPLC method with UV detection to establish a correlation between in-vitro release and in-vivo absorption data. Results: Similarity factor (f2) and dissimilarity factor (f1) were determined for the time intervals of 5, 10, 15, 45, 60, 75, 90, 105 and 120 min and the obtained values were 65.17%, 59.37%, 63.62%, 66.61%, 68.89%, 70.73%, 72.27%, 73.59%, 74.65% and 75.67% for f2 and 9.43%, 9.00%, 5.42%, 3.86%, 3.07%, 2.56%, 2.20%, 1.94%, 1,82% and 1.65% for f1 at respectve time intervals. Mean dissolution time for test and referencee products were obtained at 3.06 and 3.40 min respectively. The f2 and f1 values obtained were within the acceptable range f2 (50%-100%) and f1 (<15%). Conclusions: Comparison of dissolution profiles corroborate that the test and reference formulations are similar and there is no linear in vitro-in vivo correlation.
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    • "The absolute bioavailability ranged between 70%-96% with a mean value of 83%. Food slightly delays the time to peak serum concentration 3-4 h, but does not alter the extent of absorption [17] [18] . PTZ is highly bound to plasma proteins (>99%) mainly to serum albumin. "
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