Eleven years after the introduction of the diabetes drug rosiglitazone (Avandia), data from available clinical trials demonstrate an increased risk for MI associated with its use and suggest an unfavorable benefit-to-risk ratio, according to a meta-analysis in the June 28 issue of Archives of Internal Medicine, in advance of the July FDA meeting that will review the safety of rosiglitazone.

Rosiglitazone was approved in 1999 to treat hyperglycemia among patients with type 2 diabetes. Concerns about the cardiovascular safety of rosiglitazone first arose in 2007, when a meta-analysis demonstrated a significantly increased risk for MI and a borderline significant increase for cardiovascular death, wrote Steven E. Nissen MD, and Kathy Wolski, MPH, from the department of cardiovascular medicine at the Cleveland Clinic Foundation.

The debate over the drug's safety has continued during the past three years, and the U.S. Senate Committee on Finance recently released a report providing additional details about internal analyses conducted by the FDA and by the drug maker GlaxoSmithKline (GSK).

However, no large, definitive cardiovascular outcomes trials have been conducted with rosiglitazone. As a consequence of a 2004 court settlement in New York City, GSK was required to post clinical trial results on a public website. Nissen and  Wolski searched this GSK data and MEDLINE through February 2010 and identified 56 trials involving 35,531 patients, 19,509 of whom received rosiglitazone and 16,022 who received control medications.

Based on the meta-analysis, rosiglitazone therapy was associated with a significantly increased risk of MI by an estimated 28 percent to 39 percent, although the risk of cardiovascular death was not increased.

"An alternative analysis that included trials with no cardiovascular events found a similar hazard," the authors wrote. "Subgroups classified by study duration and comparator drug also showed elevated odds ratio estimates.

"These findings are consistent with prior meta-analyses conducted by GSK, the FDA and most independent investigators demonstrating an increased risk of MI in patients treated with rosiglitazone," they continued.

The mechanisms by which rosiglitazone may cause cardiovascular harm are not clear, the authors wrote, but could involve increases in LDL levels or genetic effects associated with the production of an enzyme linked to plaque rupture.

"The public health implications of these results are considerable. There are more than 23 million persons with diabetes in the U.S. alone and nearly 300 million worldwide. Cardiovascular disease is the leading cause of death in patients with type 2 diabetes, representing approximately 68 percent of all causes of mortality," the authors concluded.

"Although hyperglycemia has been associated with an increased risk of microvascular adverse events, there are now 12 classes of drugs that are approved to lower blood glucose levels, including insulin,” Nissen and Wolski wrote. “Because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify."