The pioglitazone controversy continues

Pioglitazone (Actose) and rosiglitazone (Avandia) are members of the thiazoladinedione (TZD) class of oral medications for type 2 diabetes. These agents have been surrounded by controversy because their predecessor in the TZD class, troglitazone (Rezulin), was withdrawn from the market because of liver toxicity. Although their beneficial effects on metabolic risk factors for macrovascular disease have long been known, outcome based data regarding protection against such events have been lacking until very recently and the Public Citizen Health Research Group has placed TZD drugs on its “do not use” list.

Recently the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) demonstrated the efficacy of pioglitazone in preventing macrovascular events. I blogged it here following presentation of the results but shortly after the announcement and before final publication a BMJ opinion piece was harshly critical of the study. My response to the BMJ commentary is here.

Now PROactive has been published in Lancet October 8 along with a commentary by Hannele Yki-Järvinen. Unlike the BMJ editorial the Lancet commentary acknowledges the clinical benefit of pioglitazone in decreasing macrovascular events. The major controversy about the PROactive results concerned the lack of statistical significance for the primary outcome and reliance on the secondary outcome. But Yki-Järvinen points out that inclusion of procedure related endpoints in the primary outcome could have biased the results against pioglitazone and implies (as I said before) that the primary outcome would have reached statistical significance with a longer follow up period, as the curves were diverging at study’s end. The commentary poses questions about the clinical significance of the increase in heart failure and how it might counterbalance the improvement in vascular outcomes.

So is it time for Public Citizen to change its “do not use” recommendation? They defend the recommendation on the basis that the TZDs “may be less effective than other drugs for diabetes and cause liver damage, weight gain, anemia and heart failure.” PROactive and other evidence suggests that this statement may be unfounded. How can the question of effectiveness of TZDs compared to other agents be answered? Because different classes of medication for diabetes have mechanisms of action which are complementary to one another it may be simplistic to ask whether one class of agents is as effective as another. It now appears that pioglitazone can join metformin as another agent capable of improving macrovascular outcomes. As for liver damage, none was found in PROactive. Weight gain (4 kg more than placebo) was seen, but the clinical significance is unknown and anemia was not mentioned. The problem of heart failure remains troubling although no new heart failure concerns were raised by the study.