Rosiglitazone and implications for pharmacovigilance

On 21 May 2007, the New England Journal of Medicine published a meta-analysis of 42 trials of rosiglitazone (Avandia, GlaxoSmithKline) for treating type 2 diabetes mellitus. It found that the drug was associated with an increased risk of myocardial infarction (odds ratio 1.43; 95% confidence interval 1.03 to 1.98; P=0.03) and death from cardiovascular causes (1.64; 0.98 to 2.74; P=0.06).1

Rosiglitazone, a thiazolidinedione, is an agonist at the peroxisome-proliferator activated receptors in cell nuclei. These receptors modulate the expression of a host of genes, and glycaemic control is achieved primarily through increased insulin sensitivity in peripheral tissues. Rosiglitazone was approved by the US Food and Drug Administration (FDA) in 1999 and by the centralised process of the European Medicines Agency (EMEA) in 2000. Its popularity has increased steadily, with more than one million prescriptions written in the one year period ending March 2006 in England alone—a 22% increase over the previous year.2 However, the recently published meta-analysis raises serious questions about the drug's safety.

Meta-analyses have unique strengths and weaknesses and this one is no exception.3 Its singular strength is the statistical power generated by data on 15 560 patients from published and unpublished trials. However, it includes clinically heterogeneous trials and criteria used …