Six Years Post-PROactive: No Lasting CV Benefits, No Excess Bladder Cancer With Pioglitazone

Shelley Wood

October 05, 2012

October 4, 2012 (Berlin, Germany) — Six-year results from the ongoing observational follow-up of the PROactive study show that macrovascular events are neither higher nor lower among patients taking pioglitazone (Actos, Takeda Pharmaceuticals) vs placebo who agreed to be tracked beyond the original study period [1]. But these same patients are also no more likely to develop bladder cancer or any other kind of malignancy, new data suggest [2].

In the original double-blind, placebo-controlled trial, patients with known macrovascular disease taking pioglitazone on top of other glucose-lowering drugs had a 10% relative risk reduction in the primary composite end point of all-cause death, MI, ACS, cardiac interventions, stroke, major leg amputation, or leg revascularization. In what became an important setback for pioglitazone, however, a numerically higher rate of bladder malignancies was diagnosed in the patients taking pioglitazone.

The original study followed patients for a mean of 34.5 months. A 10-year observational follow-up study was mandated as part of a risk management plan for pioglitazone-containing products.

Dr Erland Erdmann

Dr Erland Erdmann (University of Cologne, Germany) was listed as the first or second author on two posters here at the European Association for the Study of Diabetes 2012 Annual Meeting. Both reported six-year interim results for the follow-up study (nine years from the launch of the original randomized trial).

According to Erdmann and colleagues, including scientists from Takeda, the rate of cardiovascular and major peripheral vascular disease were high over the follow-up study: 43% of trial subjects experienced events that made up the trial's primary composite end point. But the authors report no differences between groups in the primary end point either during the six-year follow-up period or during the original trial period plus follow-up.

Of note, the decision to treat a patient with pioglitazone during the follow-up study was left to the treating physician at the close of the trial (and physicians remained blinded to trial treatment). Only 13.5% of the patients originally randomized to pioglitazone reported any pioglitazone use over the follow-up study. These data "suggest that the improved composite macrovascular morbidity and mortality outcomes seen with pioglitazone in PROactive do not persist in the absence of continued pioglitazone treatment," they conclude.

On a positive note, rates of malignancies and bladder cancers, specifically, were not statistically different between groups either for the trial-plus-follow-up period or for the follow-up period alone (although bladder cancers were numerically lower for pioglitazone-treated patients during the follow-up study).

"A mean of 2.5 years of continuous exposure to pioglitazone in the double-blind period of PROactive does not appear to be associated with an increased risk of bladder malignancy over the long term (approximately nine years of total follow-up to date)," the authors conclude.

Presenting the poster Thursday, Dr Christopher Lee, a Takeda physician, emphasized the lack of statistical power in the results seen so far.

"It will be interesting to look at the final outcomes when the study is completed, but what we did see in this analysis is that while there may be benefit accruing to patients during the randomized double-blind component of PROactive, subsequently, if the patients were withdrawn from [thiazolidinediones] TZDs, these benefits did not really persist," Lee said. "If patients continued on pioglitazone and were originally randomized to pioglitazone, that benefit tended to be maintained, although again, when we looked at the composite end point as well as the individual components of that end point, the statistical significance wasn't there."

Two other posters presented at EASD today also looked at rates of cardiovascular events among patients taking pioglitazone as compared with metformin or with placebo or active control. Both showed no increase in cardiovascular events and in some cases a reduction in major adverse cardiovascular events.

Commenting on the Erdmann study for heartwire, Dr Jeffrey B Rosen (Baptist Hospital of Miami, FL) said, "The one thing that does show up here is that there is no major finding of a cardiovascular problem, no real marker of increased cardiovascular risk."

Pioglitazone lost US patent protection earlier this year, opening the field to generics in August. A boxed warning on the drug notes that it may cause or exacerbate heart failure. Labeling also notes that the drug has been linked to an increased risk of bladder cancer. Both issues have led to lower usage of this agent in recent years.