Insulin Sensitizers and Heart Failure: An Engine Flooded with Fuel

Abstract

Since the FDA approved rosiglitazone in May 1999, there have been concerns about adverse lipid effects, edema and increased cardiovascular risk.[1] Nissen and Wolski’s 2007 meta-analysis of 42 clinical trials drew special attention to increased death and disability from cardiovascular complications in patients treated with rosiglitazone; thus many questions have been raised regarding the safety of this drug.[2] In 2007, the FDA revealed similar results in a separate meta-analysis showing a statistically significant increase in cardiovascular risk with the use of rosiglitazone.[3] The manufacturers of rosiglitazone therefore felt compelled to release an interim analysis of the RECORD Trial in 2007, with final results published in 2009. The RECORD Trial supports that the addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes does indeed increase the risk of heart failure. However, the data were inconclusive about any possible effect on myocardial infarction, and it suggested no increased risk of overall cardiovascular morbidity or mortality in those treated with rosiglitazone compared with standard glucose-lowering drugs.[4] The RECORD Trial was criticized as being underpowered and flawed by the publication of unblinded, preliminary data.[5] In June 2009, the FDA therefore mandated an adequately powered cardiovascular outcomes study for rosiglitazone known as the TIDE Trial. In July 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee joint meeting with the Drug Safety and Risk Management Advisory Committee convened. At this meeting, Dr. Nissen (Cardiovascular Medicine Chairman of the Cleveland Clinic) presented an updated meta-analysis which again demonstrated an increased risk of AMI associated with rosiglitazone.[6] In addition, Dr. Graham (Associate Director of the FDA’s Office of Drug Safety) presented the results of the retrospective cohort study discussed here, also suggesting adverse cardiovascular events associated with the use of rosiglitazone. A representative from the manufacturers of rosiglitazone was also present at the joint meeting to defend its product utilizing results from the RECORD Trial. One week following the advisory committee meeting, the FDA announced that the TIDE Trial has been placed on partial clinical hold, with no new patients eligible for enrollment until further notice. In addition, the FDA has instructed the manufacturers of rosiglitazone to update their investigators, institutional review boards and ethics committees involved in the TIDE Trial regarding any new safety information, along with information concerning the deliberations and votes of the FDA joint advisory committee meeting. The FDA is currently still evaluating all available information on rosiglitazone’s safety, in conjunction with discussions of the recent advisory committee meeting, and will update the public on the outcome of its review and its implications for both the TIDE Trial and rosiglitazone.