Diabetes Drug Is at Center of Heated Debate

Last May The New England Journal of Medicine (NEJM) published a meta-analysis of the diabetes drug rosiglitazone (Avandia) that ignited a media firestorm (2007;356:2457-2471). Nissen and Woliski concluded that the thiazolidinedione (TZD) rosiglitazone was associated with a 43% increased risk of myocardial infarction (MI) and a 64% increased risk of cardiovascular death. The Food and Drug Administration (FDA) issued an alert and required black box warnings on TZD products.

In August the FDA strengthened the warnings on TZDs, stating the drugs are not recommended for patients with symptomatic heart failure and are contraindicated in those with New York Heart Association class III or IV heart failure.

The original NEJM article and accompanying editorial sparked heated debate, multiple reanalyses of available data, and publication of interim results from the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes trial, which proved to be inconclusive.

TZD’s cardiovascular impact is important to the 16 million Americans with diabetes as heart disease is the most common cause of death among this population. The FDA approved rosiglitazone in 1999 based on clinical trials showing the drug reduced blood sugar levels in type 2 diabetes.

“Physicians are in a difficult position,” says UAB endocrinologist Fernando Ovalle, MD. “Rosiglitazone is a mainstay of diabetes treatment. It lowers blood sugar as well as insulin and sulfonylurea; improves insulin sensitivity; improves pancreatic beta-cell function and prolongs its lifespan; and is effective in patients who may not respond well to metformin, the first-line treatment."

Nissen’s and Woliski’s meta-analysis combined 42 studies with a variety of trial designs and protocols, none of which specifically targeted MI or ischemic events. “Avandia shows little or no suggestion of increased cardiovascular risks in trials that compare it with metformin or sulfonylurea,” Ovalle says. “The NEJM analysis artificially inflated the risk estimate. Two recent large, prospective, randomized, controlled trials — including ADOPT and an interim analysis of the RECORD study — did not demonstrate evidence of such a risk; in addition, a more recent meta-analysis published in The Lancet provides further reassurance” (2007; 370:1129-1136).

Ovalle warns against removing the drugs from treatment regimens without careful consideration. “Risks, benefits, and side effects vary by individual. Those without major heart disease should continue taking Avandia until further studies establish the drug’s precise risks,” he says. If a patient insists on switching, Ovalle advises opting for the TZD pioglitazone. For those who decline TZDs he recommends sulfonylurea or metformin — both have long safety records. “For some people, the only alternative to Avandia is insulin. Many of these patients will never achieve the same degree of glycemic control they enjoyed with a TZD, and suboptimal control results in significant increases in neuropathy, kidney disease, eye disease, and other microvascular complications,” he says.

“Physicians can reassure patients that the link between MI and Avandia has not been proven,” Ovalle says. On-going studies with cardiovascular-related end points may help resolve the issue. Until that information is available, clinicians can maintain a balanced and informed perspective and closely monitor their patients for cardiovascular risk factors.

For more information:
Dr. Fernando Ovalle
1.800.UAB.MIST
mist@uabmc.edu