2005 AHA Scientific Sessions: PROactive

An exploratory analysis of PROactive (Prospective Pioglitazone Clinical Trial In Macrovascular Events Study) demonstrated a significant reduction in the risk of a second coronary event in patients with type 2 diabetes who took pioglitazone.

The primary results of PROactive were announced prior to the AHA Scientific Sessions at the 41st annual meeting of the European Association for the Study of Diabetes, and published in The Lancet (Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study: a randomised controlled trial. Lancet. 2005;366: 1279–1289). In the overall study, which included 5,238 patients with type 2 diabetes at increased risk for cardiovascular events who were randomized to pioglitazone 45 mg/d or placebo and followed for a mean of 2.8 years, pioglitazone was associated with a nonsignificant 10% reduction (P=.095) in the primary end point, which was a composite of 7 types of macrovascular events. A secondary end point consisting of mortality and morbidity associated with cardiovascular disease progression was reduced by 16% (P=.027) with pioglitazone.

The analysis presented at the AHA Scientific Sessions included 2,445 patients in the original cohort who had had a previous myocardial infarction (MI). Patients were assigned to either pioglitazone or placebo in addition to optimal standard therapy with antidiabetic, lipid-modifying, and antihypertensive medications. Fifty-five percent of the study group were on statin therapy at baseline, which increased to 63% by the end of the study.

"This is the first drug in diabetes which has been shown... to decrease mortality, myocardial infarction [MI], and acute coronary syndrome [ACS]," said Erland Erdmann, MD, lead investigator of PROactive and professor of medicine at the University of Koeln in Germany. "I think it is of utmost importance that this drug lowers all of the cardiovascular risks, especially in those patients who have the most serious prognosis."

According to Dr Erdmann, pioglitazone attacks multiple cardiovascular risk factors, and its effects include an increase in high-density lipoprotein cholesterol and decreases in triglycerides, HbA_1c values, blood glucose, C-reactive protein, and blood pressure. The improvements in lipid values appear to be unique to pioglitazone among the insulin sensitizers, he added.

Reports of serious heart failure were increased in pioglitazone recipients versus placebo recipients, but there was no difference in the absolute number of deaths (1.8% vs 1.7%) in those patients, said Dr Erdmann. The increase in heart failure diagnoses among the pioglitazone recipients may have been a result of significantly more cases of edema in the pioglitazone group, some of which were mistakenly diagnosed as heart failure, he said.

According to Jorge Plutzky, MD, director of the Vascular Disease Prevention Program at Brigham and Women's Hospital in Boston, Mass, several lines of evidence suggest that PPAR-gamma activation may modulate inflammation and atherosclerosis and may have direct effects on the vessel wall. Unfortunately, no analysis is available on the original primary end point for the subgroup of patients who experienced MI. It is also possible that inclusion of leg amputation and leg artery bypass in the primary composite end point may have blunted the beneficial effect of pioglitazone, which may act preferentially to reduce the risk of coronary outcomes, Dr Plutzky added.