The diabetes drug Avandia is back on the hot seat this week, with two new studies published Monday suggesting that it may increase the risk of heart attack and other cardiovascular problems. The news comes just a few weeks before a scheduled FDA hearing on whether Avandia should stay on the market.
The drug was first approved to treat diabetes in 1999 and quickly became a blockbuster, with sales of $2.4 billion in 2006. But the FDA put a warning label on the drug in 2007, after a study by Cleveland Clinic cardiologist Steven Nissen first suggested that Avandia (also known as rosiglitazone) could raise the risk of heart attack and death.
The FDA decided then that there was not enough evidence pull Avandia from the market, but the controversy over its safety has continued. A Senate investigation earlier this year, for example, criticized the agency for overlooking concerns about Avandia raised by members of its staff.
On Monday, the Archives of Internal Medicine published an updated version of Nissen’s study. In it, he analyzed 56 drug trials involving 35,531 patients, 19,509 of whom took Avandia. The researchers found that the drug increased the risk of heart attack by up to 39 percent.
And in a separate study published Monday by the Journal of the American Medical Association, FDA researcher David Graham and his colleagues analyzed the Medicare records of 227,571 patients treated with either Avandia or with a similar drug, called Actos. Both Avandia and Actos are members of a class of drugs called thiazolidinediones (TDZs). Graham found that patients who took Avandia were 27 percent more likely to have a stroke, 25 percent more likely to have heart failure and 14 percent more likely to die during the study period than were those who took Actos.
Graham says that the study is the largest ever done of Avandia use.
“It’s not a sample of patients, it’s all of the patients who were in Medicare and had enough Medicare history,” he said. “So it’s nationally representative […] It’s everyone who could be studied.”
In an editorial accompanying the study, Dr. David Juurlink of the University of Toronto wrote “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.”
But GlaxoSmithKline, the maker of Avandia, said in a statement that other more reliable trials had found no evidence that Avandia was unsafe.
“Taken together, these trials show that Avandia does not increase the overall risk of heart attack, stroke or death,” the company said in a statement, according to the Washington Post.
And the news this week was not all bad for GlaxoSmithKline. In a study presented Monday at the American Diabetes Association meeting, researchers analyzing a data from yet another trial of diabetes treatments found — in contrast to the other two studies published this week — that Avandia did not raise the risk of cardiovascular ailments.
In this study, Dr. Richard Bach of Washington University School of Medicine in St. Louis analyzed four years of followup data from a trial called the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D). BARI 2D was originally designed not to test Avandia, but to test the efficacy of medication alone vs. medication plus surgery in treating diabetes. However, because some of the patients received Avandia, the researchers were able to do a post-hoc analysis of the data to see how those patients fared compared to the others.
“Our observations from BARI 2D do not suggest significant cardiovascular risk,” Bach said in a news conference.
But Graham says that the fact that the BARI 2D study was not designed to test Avandia casts doubt on these results, because of inherent design flaws such as the fact that the patients were not randomly assigned to the different categories. “This is a clinical trial that was designed for another purpose […] that makes the results less credible than an observational study.”
All of these studies, and others, are likely to come up at FDA hearings scheduled for July 13-14. Dr. Joshua Sharfstein, FDA’s principal deputy commissioner, told NPR that the agency has been busy gathering new data that have come out since 2007.
“A lot has changed since then,” he said. “So we feel that this is a very good time to do a serious assessment of Avandia’s safety.”