Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

A Meta-analysis of Randomized Trials

Lincoff, A. Michael MD
Wolski, Kathy MPH
Nicholls, Stephen J. MBBS, PhD
Nissen, Steven E. MD

Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

Corresponding Author: A. Michael Lincoff, MD, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 ([email protected]).

Author Contributions: Dr Lincoff had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lincoff, Wolski, Nissen.

Acquisition of data: Lincoff, Wolski, Nissen.

Analysis and interpretation of data: Lincoff, Wolski, Nicholls, Nissen.

Drafting of the manuscript: Lincoff, Nissen.

Critical revision of the manuscript for important intellectual content: Lincoff, Wolski, Nicholls, Nissen.

Statistical analysis: Lincoff, Wolski, Nicholls, Nissen.

Obtained funding: Nissen.

Administrative, technical, or material support: Nissen.

Study supervision: Lincoff.

Financial Disclosures: Drs Lincoff and Nissen report receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Takeda, Sanofi-Aventis, Eli Lilly, Pfizer, Centocor, Dr Reddy's Laboratory, Medicines Company, Roche, Daiichi-Sankyo, Schering-Plough, Scios, and AstraZeneca. Drs Lincoff and Nissen provide consulting for a number of pharmaceutical companies, but require them to donate all honoraria or consulting fees directly to charity so that they receive neither income nor tax deductions. Dr Nicholls reports receiving honoraria and consulting fees from Takeda, Pfizer, AstraZeneca, Novo-Nordisk, Merck Schering-Plough, Roche, and Anthera.

Funding/Support: This study was funded by a $25 000 grant from Takeda Pharma to support the statistical analyses.

Role of the Sponsor: The company had been involved in the collection of data for the original trials used for this meta-analysis and participated in the identification of adverse events from records within their database. The company provided that database of eligible trials to the Cleveland Clinic, and did not participate in the statistical analyses used for this publication. The company was not involved in preparing the manuscript and was not permitted to review or comment on the contents.

Additional Contribution: We gratefully acknowledge the assistance of Suzanne Turner, BA, Department of Cardiovascular Medicine, Cleveland Clinic, in creating the figures for this article. Ms Turner received no compensation for her work in association with this article.

JAMA: The Journal of the American Medical Association 298(10):p 1180-1188, September 12, 2007.

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 (I² = 0%; P = .87 for the composite end point and I² = 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.