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Rosiglitazone: A Thunderstorm from Scarce and Fragile Data
- Cynthia D. Mulrow, MD, MSc, Deputy Editor;
- John Cornell, PhD, Associate Editor; and
- A. Russell Localio, PhD, Associate Editor
The U.S. Food and Drug Administration (FDA) has approved many pharmacotherapies for treating diabetes on the basis of the drugs' ability to improve glycemic control. Although preventing adverse macrovascular outcomes, such as myocardial infarction, is a desirable goal for treatment of type 2 diabetes, there is no definitive evidence that any FDA-approved pharmacotherapy achieves such aims (1). Worse, recent meta-analyses suggest that rosiglitazone, a widely prescribed oral hypoglycemic agent, might increase the risk for ischemic heart disease by a small amount. We examine the fragile data underpinning that story and the challenges of summarizing trials with scarce events.
Early Storm Clouds for Thiazolidinediones
Rosiglitazone (Avandia, GlaxoSmithKline, Brentford, United Kingdom) is a thiazolidinedione (TZD)—a class of drugs that targets insulin resistance. Warning clouds about TZDs amassed quickly. Troglitazone, the first TZD, was withdrawn in early 2000—3 years after approval—because of severe cases of hepatotoxicity and death. The peroxisome proliferator–activated receptor-γ agonists rosiglitazone and pioglitazone, approved in 1999, had less hepatotoxicity but were associated with hemodilution, anemia, weight gain, edema, and increased risk for heart failure.
Thunder Rumbles
Prompted by a 2003 World Health Organization analysis of adverse event reports that suggested that TZDs might increase risk for cardiac disease, GlaxoSmithKline submitted preliminary pooled analyses to the FDA in 2005 that raised concerns about possible risk for ischemic cardiac events with rosiglitazone (2). The FDA's review of these and other data led to the first rosiglitazone label warnings about possible cardiac adverse effects other than heart failure, particularly in patients also receiving insulin (2). In August 2006, the FDA received GlaxoSmithKline's formal analysis of 42 randomized trials along with data from a large observational study. The meta-analysis suggested a possible “31% increase in cardiac ischemic events with rosiglitazone,” whereas the observational study showed no such increased risk (2–4). Faced with confusing data, the FDA biometrics …
