PROactive, a prospective, multicenter, randomized, doubleblind placebo-controlled parallel-group trial, compared up to 45 mg/day of pioglitazone (PGZ) on top of other medication (optimal treatment of diabetes, dyslipidemia and hypertension) to placebo in 5,238 patients with type 2 diabetes and macrovascular disease. The PROactive study objective was to see if the glucose-lowering agent, already known to have beneficial effects on cardiovascular disease risk factors such as HDL cholesterol, triglycerides, LDL particle size and inflammatory mediators, would reduce total mortality and macrovascular morbidity in these high-risk patients.

No prior prospective studies have demonstrated that oral diabetes agents prevent major cardiovascular events in patients with type 2 diabetes, noted lead investigator professor Erland Erdmann, MD, Universitat zu Koeln, Denmark. Previously reported PROactive results showed a nonsignificant (p=0.095) 10% relative reduction in the primary endpoint of combined all-cause mortality, non-fatal MI (excluding silent MI) and stroke. This substudy analysis, among 2,445 patients (mean age 61.8 years, 8 years since diabetes diagnosis) with MI prior to randomization, included pre-specified measures of time to fatal or non-fatal MI, time to CV death or non-fatal MI, and time to CV death, non-fatal MI or stroke.

For fatal/non-fatal MI, there was a significant advantage for pioglitzone versus placebo (95% CI 0.52, 0.99, p=0.045), and favorable trends for CV death or non-fatal MI (p=0.164) and CV death, non-fatal MI, stroke (p=0.123). In addition, non-pre-specified “exploratory” analyses showed significant pioglitazone advantages for ACS (HR 0.63, p=0.035) and time to composite cardiac endpoint (cardiac death, non-fatal MI, coronary revascularization or ACS) (HR 0.81, p=0.034).

While serious adverse events were reduced in the pioglitazone group (47.2% versus 51.0%), heart failure leading to hospitalization was higher (7.5% versus 5.2%). Misdiagnosis of edema as heart failure, Erdmann speculated, may account for that increase. He concluded that in this population of patients with type 2 diabetes and prior MI, “Pioglitazone significantly reduced the risk of a second MI and of ACS.”

Erdmann said finally, “Adding pioglitazone to the medication of 1,000 type 2 diabetes patients who have already had an MI (myocardial infarction) will prevent 22 recurrent MI and 23 ACS (acute coronary syndrome) events over 3 years.”