Clinical Investigation
Acute Ischemic Heart Disease
Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: Results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10)

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Background

Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes.

Methods

PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months.

Results

At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points (P < .05) and a trend to benefit in the sixth (P = .052), with hazard ratios of 0.79 to 0.83.

Conclusions

In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.

Section snippets

Study population

A total of 5238 adults (35-75 years of age, inclusive) with type 2 diabetes (hemoglobin A1c level above the upper limit of normal; ie, the local equivalent of 6.5% for a DCCT traceable assay) and with an established history of macrovascular disease (defined using a number of entrance criteria given below) were randomized into this prospective, double-blind, multicenter, placebo-controlled study conducted in 321 clinical sites across 19 European countries. The study was performed in accordance

Baseline demographics and characteristics

Medical history collected at baseline has been previously reported and was consistent with a study population with long-standing type 2 diabetes (mean duration of 9.5 years since diagnosis) and significant underlying cardiovascular disease (eg, 75% had hypertension, 47% had a prior MI, and 19% had a prior stroke). Importantly, nearly half had 2 or more of the cardiovascular entry criteria; and most patients were receiving at least one cardiovascular medication. There were no relevant

Main results

In this report, we provide an analysis of the risk of MACE in the patients enrolled in the 3-year PROactive study. Nearly half of all patients met at least 2 of the cardiovascular qualifying criteria, indicating that this was a seriously ill patient population that carried substantial risk for a major cardiovascular event. The outcome data revealed that pioglitazone treatment given on top of existing medication for diabetes, hypertension, and dyslipidemia resulted in statistically significant

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The study was funded by Takeda Europe R&D Centre Ltd, London, United Kingdom, and Eli Lilly and Company, Indianapolis, IN. Conflict of interest: Prof Wilcox has served as a consultant to Takeda. Dr Kupfer is an employee of Takeda Global Research and Development. Prof Erdmann has served as a consultant to and received travel expenses and payments for speaking at meetings from Takeda.

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