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AHA, ACC issue science advisory regarding cardiovascular risk with thiazolidinediones for diabetes

Thursday, March 04 2010 | Comments

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What's This? In a recently published science advisory, the American Heart Association (AHA) and the American College of Cardiology (ACC) concluded that there is insufficient evidence to determine whether the use of thiazolidinediones (TZDs) in general and rosiglitazone maleate in particular increases the risk of ischemic heart disease (IHD) events.

The advisory was issued to summarize the research to date evaluating cardiovascular risk with TZDs (rosiglitazone and pioglitazone hydrochloride) and to offer recommendations for patient management.

The AHA and the ACC noted that in May 2007, the Food and Drug Administration issued a safety alert describing a possible increase in the risk of cardiovascular (CV) events with rosiglitazone after a meta-analysis of 42 trials revealed a 43% increase in the risk of myocardial infarction (MI) and a nonsignificant increase in the risk of CV death associated with the drug.

However, the groups explained, subsequent analyses of data have yielded variable results, with some research showing an increased risk of certain CV outcomes and other research showing no such associations or yielding uncertain conclusions. In addition, most of these analyses consisted of observational studies or secondary analyses/meta-analyses of trials that were originally designed to evaluate the effect of the drug on glycemic control. 

In the only randomized controlled trial designed to evaluate the risk of CV outcomes with rosiglitazone (the RECORD trial, n=4,447), they noted, add-on therapy with the drug was noninferior to add-on therapy with metformin or a sulfonylurea for the composite outcome of hospitalization or CV death, but this trial was limited by a lower-than-anticipated event rate, poor adherence and/or a high crossover rate, and greater use of disease-modifying drugs (eg, statins and thiazides) in the rosiglitazone arm.

Regarding the use of pioglitazone, the AHA and the ACC noted that most of the published analyses do not suggest an increased risk of IHD events with the drug. Some data, including secondary endpoint data from the PROactive trial (n=5,238), suggest a reduced risk of death, MI, and stroke with pioglitazone, but the groups cautioned that these findings require additional confirmation.

Overall, the AHA and the ACC said that more data are needed to better evaluate the effect of TZDs and other diabetes drugs on the risk of IHD events. To date, there is evidence suggesting a macrovascular benefit with metformin, particularly in obese patients, and there is inconclusive evidence indicating potential harm with rosiglitazone. However, there are insufficient data to support the use of pioglitazone over rosiglitazone, and there is little or no research evaluating other diabetes drugs.

Until sufficient data for TZDs are available, the groups said that these drugs "should not be used with an expectation of benefit with respect to IHD events." In addition, they noted that both rosiglitazone and pioglitazone are associated with an increased risk of heart failure and should not be used in patients with class III/IV congestive heart failure, as specified in the drugs' prescribing information.

They added, "[P]atients who have successfully achieved recommended glycemic control with a TZD might consider remaining on their medication; however, if either the treating physician or the patient is uncomfortable continuing with a TZD, another medication could be substituted, with the recognition that the fund of knowledge about the effect of other glucose-lowering agents on IHD risk is similarly sparse."

This advisory, by Kaul S, et al., was published online ahead of print Feb. 23 by the journal Circulation.

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