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Rosiglitazone Associated with Increased Risk for MI
A common treatment for type 2 diabetes may have serious adverse cardiovascular effects.
Thiazolidinediones are peroxisome-proliferator–activated receptor-
agonists that increase insulin sensitivity in the peripheral tissues; their FDA approval was largely based on their ability to lower blood glucose levels. Rosiglitazone (Avandia), one of two approved thiazolidinediones, was introduced in 1999 and is used by many patients with diabetes to control blood glucose levels. A third thiazolidinedione, muraglitazar, was not approved for market because of concerns about an increase in cardiovascular events, and another, troglitazone, was removed from the market because of liver toxicity. To assess rosiglitazone’s effect on CV outcomes, investigators performed a meta-analysis of published and unpublished randomized studies posted on a GlaxoSmithKline website or publicly available through the FDA.
In the 42 trials reviewed, 86 MIs occurred in the rosiglitazone groups versus 72 in the control groups (odds ratio, 1.43; P= 0.03). Thirty-nine CV deaths occurred in the rosiglitazone groups versus 22 in the control groups (OR, 1.64; P= 0.06). The OR for all-cause mortality in the rosiglitazone groups was 1.18 (P=0.24). There was no evidence of heterogeneity across the trials.
Comment: This study presents disturbing data about increased risk for adverse CV events in patients taking rosiglitazone. Although the findings are based on relatively few events, and the authors did not have access to patient-level data, the CV outcomes show a trend opposite what would be expected for a drug used to control hyperglycemia. The mechanism for the observed effect is uncertain (although rosiglitazone is known to increase lipid levels), so these findings suggest caution in the use of this agent, especially given the availability of other therapies to control blood glucose levels in patients with diabetes. These findings should also raise concern about any drug that the FDA approves because of its effect on surrogate outcomes, such as glucose levels, without a thorough examination of its effect on patient outcomes. The FDA has issued a safety alert for rosiglitazone and is convening an advisory committee to consider the issue of CV risk associated with thiazolidinediones.
— Harlan M. Krumholz, MD, SM
Published in Journal Watch Cardiology May 21, 2007
Citation(s):
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from Cardiovascular Causes. N Engl J Med 2007 Jun 14; [e-pub ahead of print]. (http://content.nejm.org/cgi/content/full/NEJMoa072761)
Psaty BM and Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007 Jun 14; [e-pub ahead of print]. (http://content.nejm.org/cgi/content/full/NEJMe078099)
FDA issues safety alert on Avandia [press release]. Rockville, MD: Food and Drug Administration; May 21 , 2007.