Safety of PPAR Agonists

The thiazolidinediones pioglitazone and rosiglitazone were introduced into global markets in 1999–2000; we now have over 10 years of experience with them. The safety issues that it was fashionable to focus on at that time were abnormalities of liver function as a result of the rare but serious side effects of troglitazone, the thiazolidinedione then on the market. This turned out to be irrelavent for other thiazolidinediones without the antioxidant structure of troglitazone and has long since been forgotten in clinical practice. Many practicing clinicians felt concern, however, with the mechanisms of action of these drugs, namely to influence gene expression (1). Although the chemical effects are quite specific, in terms of binding to peroxisome proliferator– activated receptors (PPARs), concern over unknown problems in longer-term use prevented their prescription by some. However, even at the time of marketing approval, the issue of fluid retention was a recognized problem of PPAR agonists as a class, and simple clinical logic implied that this might be an issue with regard to cardiac failure, leading to licensing cautions even at the time of approval (2–4). Troglitazone was already being investigated for preservation of b-cell function at that time, and a study set up to address the issue for rosiglitazone, A Diabetes Outcome Progression Trial (ADOPT), subsequently identified another safety issue—that of bone fractures in people taking thiazolidinediones (5). Before this, but receiving little attention, a suggestion appeared that rosiglitazone was associated with an adverse cardiovascular (CV) profile specifically in regard to myocardial ischemia, this becoming a headline issue after a later publication of an integrated trial-level analysis inNew England Journal of Medicine (4,6) and resulting in a further regulatory review in the summer of 2010. This article addresses four issues: 1) evidence for genotoxicity with thiazolidinediones; 2) our knowledge about increased fracture rates; 3) the fluid retention, macular edema, heart failure issue; and 4) CV safety, in particular, in regard to myocardial infarction (MI) for rosiglitazone.