An analysis of data from multiple clinical trials has shown that people with Type 2 diabetes who take the oral drug rosiglitazone (brand name Avandia) have a 43% increased risk of having a heart attack. The results of this study, known as a meta-analysis (which combines and analyzes data from other studies), was published in the online edition of The New England Journal of Medicine (NEJM) on May 21.
Rosiglitazone is a member of the class of oral diabetes drugs called thiazolidinediones, which makes the body’s tissues more sensitive to insulin and causes the liver to release less glucose into the bloodstream. In addition to being sold as the stand-alone drug Avandia, rosiglitazone is found in Avandamet (a combination of rosiglitazone and metformin) and Avandaryl (a combination of rosiglitazone and glimepiride, a sulfonylurea drug). It is estimated that 60 million prescriptions for rosiglitazone have been written since it was approved by the U.S. Food and Drug Administration (FDA) in 1999. About 1 million Americans and 2 million people worldwide currently take rosiglitazone.
The FDA issued a public safety alert saying that people taking rosiglitazone, especially if they have heart disease or are at high risk of having a heart attack, should talk to their doctors about whether or not the drug continues to be the best choice for them. People should not stop taking the drug without consulting their doctors.
The meta-analysis, which was performed by researchers at the Cleveland Clinic, looked at data from two large trials and several small trials covering a total of 15,560 people who took rosiglitazone and 12,283 who took either a placebo (inactive drug) or a different diabetes drug. All trials included in the meta-analysis lasted at least 24 weeks; the average age of participants was 56 and the average HbA1c level was 8.2%.
The analysis found that people who took rosiglitazone had a 43% higher chance of having a heart attack and a 64% higher chance of dying from cardiovascular causes (heart disease or stroke), though this second finding was of borderline significance. The increased risk seen with rosiglitazone was the same whether the drug was being compared to a placebo or another diabetes drug.
These findings are troublesome because having diabetes already raises a person’s risk of developing cardiovascular disease. In fact, 65% of people with diabetes eventually die from some form of cardiovascular disease.
Limitations on the study included a lack of access to the original source data that the earlier clinical trial conclusions were based on. Also, the total number of cardiovascular “events” documented in the amalgamation of trials was small (86 heart attacks and 39 cardiovascular deaths in participants who took rosiglitazone vs. 72 heart attacks and 22 cardiovascular deaths in participants in the control groups). In addition, the trials examined in this study were not originally designed to explore cardiovascular outcomes linked to taking rosiglitazone.
In a joint statement, the American College of Cardiology, American Diabetes Association, and American Heart Association said that “the overall level of the risk associated with rosiglitazone appears to be small, but nonetheless one that must be considered carefully” and that “Further research will be needed in this area to provide conclusive evidence.”
The mechanism by which rosiglitazone may cause increased cardiovascular risk is not clear at this time, although the drug has been found to raise LDL, or “bad,” cholesterol by as much as 18% in other studies. It is also known to be linked to fluid retention, which can lead to congestive heart failure. Both of these potential side effects are currently disclosed in the drug’s labeling.
GlaxoSmithKline, the pharmaceutical company that manufactures rosiglitazone, issued a statement saying that it “strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations.” The company says that data it considers more reliable has shown that rosiglitazone has a similar cardiac risk profile to other diabetes drugs on the market.
The FDA is currently reanalyzing data about rosiglitazone and will soon convene an advisory panel to review the drug. Meanwhile, the organization has come under fire for failing to mandate a long-term study of rosiglitazone’s safety after its approval.
The only other approved drug in the thiazolidinedione class is pioglitazone (Actos), which was shown to reduce the risk of heart attack in a specifically-designed, large-scale trial called the PROactive study, published in the journal The Lancet in 2005. A similar study looking at rosiglitazone, called the RECORD trial, is currently under way, but results are not expected until 2009.