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Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials

A. Michael Lincoff, MD; Kathy Wolski, MPH; Stephen J. Nicholls, MBBS, PhD; Steven E. Nissen, MD
JAMA. 2007;298(10):1180-1188. doi:10.1001/jama.298.10.1180.
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Context 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.

Objective To systematically evaluate the effect of pioglitazone on ischemic cardiovascular events.

Data Sources and Study Selection 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.

Data Extraction 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.

Data Synthesis 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 (I 2 = 0%; P = .87 for the composite end point and I 2 = 0%; P = .97 for heart failure).

Conclusions 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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Figure 1. Flowchart of Pioglitazone Trials Used for the Meta-analysis
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Figure 2. Estimates of the Incidence of the Cardiovascular End Points According to Randomized Treatment Assignment to Pioglitazone or Control
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A, Kaplan-Meier curve of time to death from any cause, nonfatal myocardial infarction, or nonfatal stroke. B, Shows curve of time to serious congestive heart failure.

Figure 3. Hazard Ratios and 95% Confidence Intervals for Cardiovascular End Points in Subgroups.
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A, Numbers of events and hazard ratios for the composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke comparing pioglitazone vs control therapy. B, Numbers of events and hazard ratios for congestive heart failure comparing pioglitazone vs control therapy. Subgroups were defined according to enrollment in the PROactive trial vs all other trials in the meta-analysis, the duration of study drug treatment, and the type of drug therapy in the control groups. P values are p-for-effect modification testing for heterogeneity across the category of stratification. CI indicates confidence interval. Size of the data markers is proportional to the sample size of the trial populations. B, Rx* denotes background treatment.

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