Expert Blog

New FDA Restrictions And The Future Of TZDs

Irl B. Hirsch, MD

Even after the elimination of troglitazone from the market over ten years ago due to an increased risk of severe liver toxicity, the two remaining thiazolidinediones, rosiglitazone and pioglitazone, have been watched more closely than most new drugs on the market. It was quite clear these agents could result in weight gain, fluid retention, and even pulmonary edema. The use of insulin with thiazolidinedione treatment roughly doubles the incidence of edema and amount of weight gain, compared with either drug alone. But then the reported side effects worsened. We first heard from Steven Kahn and colleagues in the ADOPT trial that women randomized to rosiglitazone experienced increased fracture risk involving bones of the distal appendages, forearms, hands, feet, and lower legs.[1] Not too long after that, Nissen and Wolski published a meta-analysis suggesting cardiovascular risks with this drug (specifically, increased risk of myocardial infarction and near-significant increased risk of death from cardiovascular causes compared with placebo or standard drug therapy).[2]

Since then, there has been an almost unprecedented number of events taking place. Numerous studies (mostly meta-analyses) searched for similar cardiovascular dangers with pioglitazone, but none could be found. In 2007 the U.S. Food and Drug Administrations (FDA) convened an advisory committee meeting, which resulted in the addition of the possibility of ischemic cardiovascular risk to the drug’s existing boxed warning. The FDA also required the sponsors to conduct a head-to-head cardiovascular safety trial matching rosiglitazone with pioglitazone.
After new data became available and after a second FDA advisory board meeting in July of 2010, in late September the FDA announced regulatory actions stemming from those deliberations. With the new restrictions, rosiglitazone will only be available for those not already taking it only if they are unable to achieve glycemic control using other diabetes medications, and, in consultation with their health care professional, decide not to use pioglitazone for medical reasons. Current users of rosiglitazone will be able to continue using the medication if they appear to be benefiting from it and acknowledge that they understand these newly elucidated risks. Doctors will need to attest and document their patient’s eligibility (although we do not yet know what administrative burden this will entail); patients will have to review statements describing the cardiovascular safety concerns. Suffice it to say, the head-on-head trial for rosiglitazone vs. pioglitazone was discontinued.
It will be interesting to see how many patients will be using rosiglitazone a year from now. Two years? In Europe, the European Medicines Agency took the drug off the market altogether.
So where does that leave us now? Is not having rosiglitazone at your easy disposal going to make treating your type 2 patients more difficult? Or did the FDA rulings not go far enough and perhaps the drug should have been completely eliminated as was done in Europe?
Over the years, even prior to the Nissen/Wolski meta-analysis, I have been outspoken against thiazolidinediones. I never understood why—with metformin, sulfonylureas, and insulin available—we needed this class of drugs which makes fat people fatter and more edematous. Perhaps I would feel differently if we had a prospective and randomized trial showing an improvement in cardiovascular events as a primary outcome. In my own practice where most patients with type 2 diabetes requiring insulin were provided either rosiglitazone or pioglitazone the weight gain we saw was historic. We learned this is probably not the best place to use this drug, but then we see few patients in our academic diabetes clinic not requiring insulin. But even earlier in the progression to beta cell deficiency, would I consider a GLP-1 analog or a DPP-IV inhibitor prior to a thiazodinedione? The answer is yes, for all of the reasons we now understand about incretin therapy. That is not to say we may not see another New England Journal of Medicine meta-analysis about one of these drugs (or even an older drug!) at some point in the future. But for now, I have no problems with the new FDA restrictions, and at least in my clinic this will have no impact: we don’t use these drugs at all as it is.
Would be curious to hear your thoughts.