The Rosiglitazone story: Lessons from an FDA Advisory Committee Meeting

Abstract

Thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor-γ agonists that reverse or ameliorate many of the adverse cardiovascular effects of diabetes mellitus. These agents increase insulin sensitivity, enhance glucose control, provide some improvement in lipid profile, suppress inflammatory and cardiovascular risk markers, reduce proinflammatory cytokines, augment endothelial function, and improve vascular structure and function. As for clinical endpoints, rosiglitazone substantially reduced the development of diabetes in patients with prediabetes and pioglitazone decreased mortality, stroke, and myocardial infarction (MI) rates in patients with type 2 diabetes. Yet, despite reducing fasting plasma glucose levels to normal, there has been evidence, too, of more adverse cardiovascular events with rosiglitazone versus placebo or active therapy (merformin or glyburide), including more congestive heart failure (HF). In recent months, a controversy has emerged over the ischemic risks associated with rosiglitazone treatment. Nissen et al. presented the results of a meta-analysis of treatment trials comparing rosiglitazone versus placebo or other antidiabetic therapy for type 2 diabetes. Rosiglitazone was associated with a significant 30%-40% greater risk of MI and a borderline-significant increased risk of death from cardiovascular causes. Accompanying the Nissen study were interim findings from the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial of add-on rosiglitazone therapy in patients with type 2 diabetes. The unplanned interim analysis was inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes, but rosiglitazone was associated with an increased risk of HF. Based on these data, the U.S. Food and Drug Administration (FDA) issued a safety alert on rosiglitazone on May 21, 2007, urging patients taking rosiglitazone, particularly those with underlying heart disease or at high risk for MI, to discuss the new information with their doctor to make "individualized treatment decisions." The alert noted that the FDA had not concluded there is a causal relationship between the drug and the reported safety concerns nor is it advising that prescriptions be discontinued.