The rise and fall of rosiglitazone

Extract

This editorial refers to ‘Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial’^†, by M. Komajda et al. on page 824

Komajda et al. have described the increased incidence of congestive heart failure (CHF) in patients treated with rosiglitazone in the RECORD Trial (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes).¹ This study is the latest chapter in the tortured saga of rosiglitazone, a drug that was once the largest selling diabetes therapy in the world.² The rise and fall of rosiglitazone raises critical scientific and ethical questions about drug development and marketing, with profound consequences, including the recent decision by US regulatory authorities to require cardiovascular outcome studies for all new diabetes drugs.³

Rosiglitazone and related thiazolidindiones (TZDs) are modulators of nuclear receptor proteins known as peroxisome proliferator-activated receptors (PPARs) that function as transcription factors regulating expression of genes. Of the many subclasses of PPAR modulators, two types have been marketed, PPARα agents, such as fenofibrate, that affect lipid metabolism, and PPARγ agents, such as rosiglitazone, that act as insulin sensitizers. One marketed TZD, pioglitazone, is considered a dual PPAR agonist, with modest α effects and strong γ effects. PPARs influence a large number of genes, perhaps 100 or more, most of which have unknown biological effects. Accordingly, the effects of these agents are unpredictable and can result in unusual toxicities. Indeed, during the past decade, >50 PPAR agonists have failed during clinical development, some due to cardiotoxicity,⁴ although few publications have detailed the precise toxicity encountered. One agent, muraglitazar, was recommended for approval by a US Food and Drug Administration (FDA) advisory panel, but ultimately not approved after a meta-analysis of clinical trials obtained from FDA documents revealed an approximate doubling of adverse cardiovascular outcomes.⁵