Rosiglitazone use increases odds of myocardial infarction, confirmed

Key Points

A systematic review and meta-analysis evaluating the effects of rosiglitazone on cardiovascular morbidity and mortality confirmed the finding of increased odds of myocardial infarction with rosiglitazone.

An increased risk was previously demonstrated in a 2007 meta-analysis published in the New England Journal of Medicine by the same authors, at which time they found a 43% increased odds of myocardial infarction.

This new meta-analysis, which contains additional randomized controlled trial data, including more than 4,000 participants from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, was published on-line ahead-of-print on June 28, 2010 in the Archives of Internal Medicine.

In total, researchers identified 56 randomized controlled trials (n=35,531 total participants) of which 19,509 received rosiglitazone and 16,022 received some form of control therapy.

WHAT THE META-ANALYSIS FOUND

Upon meta-analysis the investigators found rosiglitazone therapy significantly increased the odds of myocardial infarction (n=41 trials; OR=1.28; 95% CI, 1.02–1.63; P=.04) compared with control. Cardiovascular mortality appeared, however, unaffected (n=26 trials; OR=1.03; 95% CI, 0.78–1.36; P=.86). This latter finding was consistent with the author's findings from their previous meta-analysis (OR=1.64; 95% CI, 0.98–2.74; P=.06).

In response to those citing the RECORD trial as evidence of rosiglitazone's cardiovascular safety, Steven E. Nissen, MD, lead author of the paper and co-author Kathy Wolski, MPH, note, "That study was limited by low event rates, which resulted in insufficient statistical power to confirm or refute evidence of an increased risk for ischemic myocardial events." On its own, the RECORD trial did not show a statistically significant increase in myocardial infarction risk (OR=1.15; 95% CI, 0.80–1.66).

Exclusion of the RECORD trial from their meta-analysis did not result in any meaningful changes in overall conclusions (OR=1.39; 95% CI, 1.02–1.89; P=.04 for myocardial infarction and OR; 1.46; 95% CI, 0.92–2.33; P=.11 for cardiovascular mortality). Other sensitivity (or "what-if") analyses including stratification or restriction by allocation ratio, trial duration, or type of control also failed to alter the meta-analysis' overall conclusions.

PIOGLITAZONE

While admitting that the mechanism behind rosiglitazone's detrimental effects was not well understood, Dr Nissen suggested that rosiglitazone's ability to increase low-density lipoprotein cholesterol (LDL-C) levels or its ability to activate a gene associated with production of matrix metalloproteinase 3 (an enzyme linked to plaque rupture) are both plausible explanations. Neither of these deleterious effects are associated with the other FDA-approved glitazone, pioglitazone.

Pioglitazone has not been shown to have similar cardiovascular harm to rosiglitazone. In fact, a past meta-analysis found that the relative hazard of myocardial infarction was less with pioglitazone than control (HR=0.81; 95% CI, 0.64–1.02; P=.08) and the hazard of the combined end point of death, myocardial infarction, and stroke was significantly reduced (HR=0.82; 95% CI, 0.72–0.94; P=.005).

The paper concludes by suggesting, "The current findings suggest an unfavorable benefit-to-risk ratio for rosiglitazone." FDA plans on further review of the cardiovascular safety of rosiglitazone this month.

SOURCES

Nissen SE, Wolski W. Rosiglitazone revisited: An updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med. Published online June 28, 2010.

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–2471.

Home PD, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373(9681):2125–2135.

Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007; 298(10):1180–1188.

FDA. FDA Drug Safety Communication: Ongoing review of Avandia (rosiglitazone) and cardiovascular safety. February 22, 2010. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm201418.htm#Healthcare/. Accessed on June 29, 2010.