Pioglitazone Beneficial in Diabetes Patients With Previous MI?

April 23, 2007


April 23, 2007 (Koln, Germany) - A new subgroup analysis of the PROactive trial of pioglitazone in diabetes patients has shown that in patients with previous MI, the drug reduced the occurrence of recurrent MI, but two other prespecified composite end points defined for this subgroup (cardiovascular death/MI and cardiovascular death/MI/stroke) were not significantly different between the pioglitazone and placebo groups.

In addition, the primary composite end point in the main PROactive study (the time to first occurrence of macrovascular events or death) did not show a significant difference in this subgroup. But there were significant reductions in two nonprespecified end points--ACS and a cardiac composite end point comprising nonfatal MI (excluding silent MI), coronary revascularization, ACS, and cardiac death.

The main adverse event of concern with this class of drug, heart failure, was increased in the pioglitazone group in this subgroup, but there was no statistically significant difference in fatal heart failure.

This latest analysis from the PROactive study is published in the May 1, 2007 issue of the Journal of the American College of Cardiology [1]. The authors, led by Dr Erland Erdmann (Medizinische Klinik III der Universität zu Köln, Germany), conclude: “The benefit of pioglitazone is clear from the Kaplan-Meier curves for both time to fatal/nonfatal MI and time to the composite cardiac end point. If the study duration had been longer, continued divergence of the curves (if it occurred) would have strengthened our findings."

But an accompanying editorial by Dr Jukka Westerbacka (University of Helsinki, Finland) is more cautious [2]. Westerbacka says that: “Pioglitazone treatment in patients with previous MI may provide modest additional benefit, which could have been more evident in the PROactive substudy if the number of patients were larger and the duration of the study were longer. However, clinicians should weigh the benefits against the fact that the incidence of heart failure is increased, which is especially important in patients with a history of MI.”

Commenting on the study for heartwire , Dr Nick Freemantle (University of Birmingham, UK) was also reluctant to read much into the current results. He said: “As the overall PROactive study did not achieve its primary end point, all subgroup analyses should be thought of as purely exploratory, and the result of this subgroup analysis isn’t even that positive, with a marginally significant p value. There may be something going on, but this is not a very good estimate, and this study is not really telling us very much with any great certainty."

Freemantle said the heart-failure data from PROactive and other studies of these agents were “somewhat reassuring." “There is still some uncertainty about the safety of thiazolidinediones in terms of edema and heart failure, but the PROactive study and other studies conducted with these agents have shown that any such effect is quite small. I think a large effect on heart failure can now be excluded, but I don’t think these concerns have disappeared completely." He added: “There may be a small increase in edema and heart failure, but this has to be balanced by the clear reduction in HbA1c levels of about 0.5% seen with these drugs."

Freemantle noted that the thiazolidinediones should be considered as one possible choice of glucose-lowering drugs to be used for the treatment of diabetes. “They do bring down HbA1c levels effectively, but this has to be balanced by the costs and the fact that they increase body weight. If you look at all the studies coming out, thiazolidinediones do not have any clear advantages over other diabetes drugs. And while the current study does not preclude the use of pioglitazone in patients with previous MI, neither does it give clear-cut evidence to use it in this population," he added.

The PROactive study

The main PROactive study randomized 5238 patients with type 2 diabetes and macrovascular disease to either pioglitazone or placebo in addition to their other glucose-lowering and cardiovascular medication. Patients were followed for a mean of 2.85 years. The primary end point--the time to first occurrence of macrovascular events or death--was not significantly reduced by pioglitazone, but the secondary end point of death/MI/stroke was reduced.

Erdmann et al note that the current subgroup analysis, with 2445 patients who had had a previous MI, represents one of the largest groups of patients with type 2 diabetes and previous MI to be examined in a prospective randomized study.

They point out that three composite end points had been prespecified for this previous-MI subgroup: fatal or nonfatal MI (excluding silent MI); cardiovascular death or nonfatal MI (excluding silent MI); and cardiovascular death, nonfatal MI (excluding silent MI), or stroke. Results showed that the first of these prespecifed end points was significantly reduced, and the other two showed positive trends.

PROactive previous-MI subgroup: Results of prespecified end points

Prespecified end points Pioglitazone, n=1 230 (%) Placebo, n=1 215 (%) HR (95% CI) p
Recurrent MI 5.3 7.2 0.72 (0.52–0.99) 0.0453
CV death/MI 9.3 0.9 0.85 (0.66–1.09) 0.2013
CV death/MI/stroke 11.1 13.0 0.85 (0.67–1.06) 0.1493


Two nonprespecified end points also showed significant reductions with pioglitazone. These were the occurrence of ACS (HR 0.63; p=0.035) and the composite cardiac end point of nonfatal MI, coronary revascularization, ACS, and cardiac death (HR 0.81; p=0.034). All of the other end points showed positive trends but did not reach significance.

In this subgroup of patients with a previous MI, there was an increase in heart failure in the pioglitazone group, but no statistically significant difference in fatal heart failure.

PROactive previous-MI subgroup: Incidence of heart failure

Heart-failure definition Pioglitazone (%) Placebo (%) Time to CHF, hazard ratio (p)
Any heart failure 13.5 9.6 1.43 (0.003)
Hospitalization for CHF 7.5 5.2 1.45 (0.02)
Fatal heart failure 1.4 0.9 1.52 (0.283)


Erdmann et al conclude that these results “indicate that pioglitazone reduces the risk of adverse cardiac outcomes, including MI, in these patients."

But in his editorial, Westerbacka says the three different end points in this subgroup analysis, which are different again from the main end points defined for the main trial, “could be criticized for resembling a fishing approach." He suggests that the reason that only the MI end point was significantly reduced with pioglitazone may be that there was more heart failure in the pioglitazone group, contributing to cardiovascular death, which was included in the other composite end points.

Noting that patients with previous MI are at increased risk of heart failure, Westerbacka comments: “For clinicians, the increased risk of heart failure with glitazones means more careful decision-making when optimizing the treatment of type 2 diabetic patients with previous MI. In general, the number-needed-to-treat should be accompanied by the number-needed-to-harm to better estimate the benefits of the treatments.”

  1. Erdmann E, Dormandy JA, Charbonnel B. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction. Results from the PROactive study. J Am Coll Cardiol 2007; 49:1772–1780.

  2. Westerbacka J. PROactive in patients with type 2 diabetes and previous myocardial infarction. Swinging the sword of Damocles? J Am Coll Cardiol 2007; 49:1781–1782.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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