Canadians Document Excess Mortality with Rosiglitazone (Avandia)

By Peggy Peck
TORONTO, Dec. 11 -- More than three years of thiazolidinedione monotherapy for diabetes was associated with a 40% increase in relative risk of myocardial infarction and a 29% increase in relative risk of death, researchers here found.The thiazolidinedione treatment's adverse effects were "primarily with rosiglitazone (Avandia)," Lorraine I. Lipscombe, M.D., M.Sc., of the University of Toronto, and colleagues, concluded in the Dec. 12 issue of the Journal of the American Medical Association. There was also a 60% rise in the relative risk of congestive heart failure associated with rosiglitazone.
Dr. Lipscombe and colleagues concluded that the excess cardiovascular events appeared to be limited to rosiglitazone, But they also said they found no evidence that pioglitazone (Actos) reduced the risk of MI and cardiovascular death, a protective effect reported by other researchers.
"In contrast to clinical trial data, which suggested that both pioglitazone and rosiglitazone are associated with an increased risk of congestive heart failure, we observed this association only with rosiglitazone," they wrote.
Last month the FDA ordered that an MI warning be added to the black box on the rosiglitazone label, and it asked for extensive long-term trials to determine the drug's cardiovascular safety. Both rosiglitazone and pioglitazone carry black box warnings for congestive heart failure.
The nested case-control study of almost 160,000 diabetes patients age 66 or older who were taking at least one hypoglycemic agent was the latest analysis to report a 40% or greater increase in MI among patients taking rosiglitazone, a finding first reported by Steven Nissen, M.D. of the Cleveland Clinic, in a meta-analysis published online by the New England Journal of Medicine more than six months ago.
Dr. Lipscombe and colleagues compared risks of MI, congestive heart failure, and death between patients treated with thiazolidinediones -- rosiglitazone and pioglitazone -- and other oral hypoglycemic agent combinations, after matching and adjusting for prognostic factors.
During a median follow-up of almost four years, 12,491 patients were hospitalized at least once for heart failure, 12,578 for MI, and there were 30,265 deaths.
Over four years, the estimated numbers needed to harm with thiazolidinediones therapy were 34 patients for congestive heart failure, 26 for MI, and 22 for death, Dr. Lipscombe wrote.
The study, the authors wrote, was "to our knowledge the first study to evaluate thiazolidinedione-related outcomes among an entire population of older patients with diabetes." And the study was, they added, the first to "document an increase in mortality among thiazolidinedione users.
"Although we could not determine the cause of death in our study, the fact that cardiovascular events were also increased with thiazolidinediones suggests a possible cardiovascular etiology in this older, high-risk population," they wrote.
Dr. Nissen, who wasn't involved in the study, said the Canadian data provided a fairly good snapshot of the rosiglitazone effect in a real-world clinical setting. Dr. Nissen's meta-analysis was based on published data from 42 clinical trials.The study was funded by the Ontario Ministry of Health and Long-Term Care. Dr. Lipscombe is supported by a clinician scientist award from the Canadian Diabetes Association and the Canadian Institutes of Health. Dr. Nissen reported receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, sanofi-aventis, and Eli Lilly. He also consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction.
Primary source: Journal of the American Medical AssociationSource reference:Lipscombe LI, et al "Thiazolidinediones and cardiovascular outcomes in older patients with diabetes" JAMA 2007; 298: 2634-2643.