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Actos Benefits Recent Heart-Attack Patients with Diabetes

November 26, 2005

Actos (pioglitazone) has been shown to reduce the risk of another heart attack among diabetic patients recovering from a heart attack. In a recent study, Actos added to standard therapy for glucose and lipid control proved superior in preventing repeat heart attacks.

Analysis of a data subset from 2,445 patients enrolled in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) trial revealed that taking Actos was associated with a 28% lower risk of recurrent myocardial infarction (MI; P=0.045), according to Erland Erdmann, MD, of the University of Köln in Germany.

Actos is in a class of drugs called thiazolidinediones. Thiazolidinediones raise the body's sensitivity to insulin, by binding to and activating a receptor (the peroxisome proliferator-activated receptor-gamma).

Subset Analysis is Key

The subset analysis of data, presented at the American Heart Association (AHA) meeting in Dallas in November, provided a new perspective on Actos's benefits for recent MI patients that had not been evident from the main PROACTIVE study results. In these results, revealed at the European Association for the Study of Diabetes last September, researchers mainly noted that the trial did not meet its primary endpoint.

All participants in the subset analysis had had an MI within 6 months before randomization. Participants received treatment according to European Association for the Study of Diabetes guidelines. A total of 55% of participants received statin therapy at baseline and 63% were receiving statins at the study's end, Dr Erdmann said.

Actos was associated with a 37% relative decrease in the risk of acute coronary syndrome (P=0.035) and a 19% relative decrease in the composite endpoint of non-fatal MI, coronary revascularization, acute coronary syndrome and death (P=0.034).

The primary endpoint in the main PROACTIVE study was a 20% improvement during the time from randomization to the participant's next cardiovascular event (i.e., a composite of all-cause mortality, non-fatal MI, stroke, acute coronary syndrome, coronary revascularization, limb revascularization or amputation above the ankle).

In the main PROACTIVE study, Actos was associated with only a 10% improvement , thus missing the primary endpoint. However, these results did confirm that Actos was associated with a 16% reduction in risk of death or recurrent heart attack.

PROACTIVE was conducted in 19 European countries and involved 5,238 diabetic participants with prior MI. Participants were randomized either to the highest tolerated dose of Actos (up to 45 mg) or placebo, on top of standard therapy (including insulin, when indicated). Patients were followed for an average of 2.8 years.

One problem with the earlier results was the issue of increased congestive heart failure among patients in the Actos arm, according to AHA president Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado Health Sciences Center in Denver.

Dr Erdmann noted that the subset analysis more clearly elucidates the heart failure question. In total, 63 of the 1,215 patients receiving placebo and 92 of the 1,230 patients receiving Actos were hospitalized for treatment of congestive heart failure.

"We know that patients with diabetes and heart failure have a particularly bad prognosis, but when we looked at mortality, in the control group exactly one-third of the congestive heart failure patients died, but in the [Actos] group 22 of the 92 patients died," said Dr Erdmann, according to MedPage Today. "That was less than one-fourth."

Because Actos promotes edema by directly stimulating sodium reabsorption in the kidney, the likely explanation for these results is that patients on the Actos arm were "misdiagnosed with congestive heart failure. They really had edema," said Dr Erdmann. At any rate, he added, "there was no excessive death due to heart failure in the [Actos] arm."

The PROACTIVE trial was funded by Takeda Pharmaceuticals, which markets Actos.

Sources: AHA: Actos More Effective in Patients with Recent Heart Attacks, MedPage Today, 16 November 2005.
The effect of pioglitazone on recurrent myocardial infarction in 2445 patients with type 2 diabetes and previoius myocardial infarction-results from the PROactive study, Erdmann E et al. American Heart Association Scientific Sessions late-breaking news, 16 November 2005.

Posted: November 2005

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