Secondary Prevention of Macrovascular Events in Patients With Type 2 Diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A Randomised Controlled Trial

Dormandy JA, Charbonnel B, Eckland DJA, et al. Lancet. 2005;366:1279-1289.

Compared with healthy individuals, people with diabetes have a 2- to 4-fold increased risk for macrovascular events. Several large randomized trials have demonstrated clear effects of tight glycemic control on the prevention of microvascular complications. However, those same studies failed to demonstrate a relationship between tight glycemic control and the prevention of macrovascular complications. Accordingly, there is a great need to reduce the incidence of macrovascular complications among people with diabetes. Previous work with pioglitazone has suggested that it may have a positive effect cardiovascular risk factors and thereby decrease morbidity and mortality associated with diabetic macrovascular complications. Thus, the goal of this study was to determine whether pioglitazone can affect cardiovascular morbidity and mortality among people with type 2 diabetes. Safety and tolerability were also assessed.

A total of 5238 patients were recruited for this study. In order to be eligible to participate, patients had to have a previous history of macrovascular disease, including: myocardial infarction (MI) or stroke at least 6 months prior to study entry, percutaneous coronary intervention or coronary bypass surgery at least 6 months before recruitment, acute coronary syndrome at least 3 months before recruitment, or objective evidence of either coronary artery disease or obstructive arterial disease of the leg. Participants were predominantly male (66%), older (average age = 62 years), and in suboptimal glycemic control (average A1C = 7.8). Many patients also were overweight and had a history of hypertension, dyslipidemia, and microvascular complications.

Patients were randomly assigned to receive either pioglitazone or placebo in addition to their regular diabetes medications. Patients assigned to the pioglitazone group were started on a dose of 15 mg for the first month, 30 mg for the second month, and 45 mg for the remainder of the study. Medications could be adjusted as needed to reach glycemic targets. Study participants were seen monthly for the first 2 months. Following that, they were seen bimonthly for the next year. After 1 year, patients were seen every 3 months until study conclusion. The primary study endpoint was a composite measure of time from randomization to a variety of events, including: all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention of the leg arteries, or amputation above the ankle. Secondary endpoints included: a composite measure of time until death from any cause, first MI, or first stroke; cardiovascular death; and time to individual components of the primary composite endpoint.

Results of the study showed that pioglitazone was well tolerated, with 89% of patients reaching the target dose of 45 mg at the 2-month follow up visit, compared with 91% in the placebo group. Adherence with pioglitazone was greater than 95%. In terms of macrovascular endpoints, more control patients had at least one macrovascular event in the primary composite endpoint than their counterparts in the pioglitazone group did, although this finding did not reach statistical significance. Although the primary endpoint was not met, the secondary composite endpoint of all-cause mortality, MI, and stroke did reach statistical significance (P = .027). A total of 514 events occurred in the pioglitazone group, and a total of 572 events were documented in the placebo group. Further, the use of pioglitazone reduced the need to add insulin to the therapeutic regimen, compared with the placebo group.

This study did not meet its primary endpoint, but treatment with pioglitazone did successfully reduce the composite of all-cause mortality, first stroke, or first MI. For every 1000 patients taking pioglitazone, 21 first strokes, MIs, or deaths could be prevented over a period of 3 years. Treatment with pioglitazone also improved glycemic control and lipids (independent of the effects of other lipid-lowering agents). The mechanism of this effect is unclear because the pioglitazone group had better glycemic control, lipid values (HDL and triglycerides), and blood pressure control, and any of these factors could have contributed to the effect.