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Rosiglitazone-related heart risks reported in 2 newly published analyses; third study disputes association with increased heart risks

Tuesday, July 13 2010 | Comments

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What's This? Two studies published in leading medical journals indicate that rosiglitazone maleate is associated with serious heart-related risks, whereas the results of a third study seem to oppose those findings.

The cardiovascular (CV) safety of rosiglitazone has been the subject of debate since 2007 when researchers suggested that the drug might be associated with an increased risk of myocardial infarction (MI) or death.

Two of the latest studies addressing this issue were published online June 28 as early-release articles. The first study, which was published in JAMA, was led by Dr. David Graham, a Food and Drug Administration drug safety expert who has been in favor of withdrawing rosiglitazone from the market.

Dr. Graham and his team reviewed data for 227,571 Medicare patients (mean age, 74 years) who started taking rosiglitazone or pioglitazone hydrochloride, another member of the thiazolidinedione drug class, during the period beginning July 2006 and ending June 2009. These patients were followed for as long as 3 years.

The study's individual primary endpoints were acute MI, stroke, heart failure (HF), and death; the composite endpoint included all 4 of these individual endpoints.

In all, 8667 endpoints were observed during the study period. Rosiglitazone was associated with an increased risk of stroke, HF, and death and an increased risk of the composite endpoint as compared with pioglitazone. Specifically, the adjusted hazard ratio (HR) for rosiglitazone (vs pioglitazone) was 1.27 (95% CI, 1.12-1.45) for stroke, 1.25 (95% CI, 1.16-1.34) for HF, 1.14 (95% CI, 1.05-1.24) for death, and 1.18 (95% CI, 1.12-1.23) for the composite endpoint. The corresponding HR for acute MI was 1.06 (95% CI, 0.96-1.18). 

The study authors pointed out that the lack of an increased risk of MI with rosiglitazone was also observed in 2 other studies conducted among elderly people, adding that most studies that have reported an increased risk of MI with rosiglitazone were conducted in younger participants.

In an accompanying editorial, Dr. David Juurlink of the Sunnybrook Health Sciences Centre in Toronto said, "Whether rosiglitazone and pioglitazone really do have different CV safety profiles is an intriguing question but one with a misplaced focus. Accumulating concerns about rosiglitazone make it difficult to advance a cogent argument regarding why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative."

In the second study, which was published by the Archives of Internal Medicine, the authors who conducted the original rosiglitazone study that started the controversy in 2007 performed an expanded analysis of the available data.

Dr. Steven Nissen, chairman of the department of cardiovascular medicine at Cleveland Clinic, and Kathy Wolski conducted a meta-analysis of 56 trials that included 35,531 patients. All trials included in the analysis were randomized controlled trials of rosiglitazone that lasted >=24 weeks and reported CV adverse events.

Overall, rosiglitazone was associated with a significantly increased likelihood of MI (odds ratio [OR], 1.28 [95%CI, 1.02-1.63]; P=.04), but not an increased risk of CV mortality (OR, 1.03 [95% CI, 0.78-1.36]; P=.86). After excluding the RECORD trial, a study that the authors noted has raised concern in the past regarding its design and execution, the corresponding ORs were 1.39 (95% CI, 1.02-1.89; P=.04) and 1.46 (95% CI, 0.92-2.33; P=.11).

When estimating the number needed to harm, the authors determined that 1 additional MI would occur for every 52 people (including the RECORD trial) or 37 people (excluding the RECORD trial) who took rosiglitazone for 5 years.

"The results of the current meta-analysis suggest an unfavorable benefit-to-risk ratio for rosiglitazone use," the researchers remarked.

"Because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify," they concluded.

However, in a third study, the results of which were presented in Orlando, Fla., at the American Diabetes Association's 70th Scientific Sessions, researchers reported that rosiglitazone poses no significantly increased risk of MI, stroke, or death.

Sheryl Kelsey of the University of Pittsburgh Graduate School of Public Health and colleagues conducted a post hoc analysis of the BARI 2D study, a landmark trial that focused on patients with both diabetes and heart disease. The researchers evaluated the effects of rosiglitazone in reducing deaths or deaths and CV events (MI and stroke) combined in 2,368 individuals with type 2 diabetes and stable coronary artery disease.

When compared with the patients who were not taking any thiazolidinediones, those who were treated with rosiglitazone did not have an increased risk of death or MI, based on 4.5 years of follow-up data. In fact, the rate of MI, stroke, and death was approximately 28% lower among the patients who were treated with rosiglitazone.

The BARI 2D study was partly funded by GlaxoSmithKline Plc, the firm that markets rosiglitazone under the brand name Avandia, and by the National Institutes of Health.

In response to the JAMA and Archives studies, GSK released a statement saying that results from 6 controlled clinical trials have been published since the FDA committees conducted their safety review in 2007, and "[t]aken together, these trials show that rosiglitazone does not increase the overall risk of heart attack, stroke, or death."

The firm also noted that additional observational studies have been published since 2007, and a review of these studies indicates no difference in the risk of MI between rosiglitazone and pioglitazone.

In August 2007, the labels of both drugs were updated with black box warnings about congestive HF risk. In November 2007, rosiglitazone's label was updated with a warning about myocardial ischemia risk and precautions regarding co-administration with insulin or nitrates.

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