Avandia, a controversial but popular drug used to control diabetes, increases the risk of heart attack, stroke, heart failure and death, researchers reported today in a study published in the Journal of the American Medical Association.
Researchers who carried out the JAMA study estimate the drug caused 48,000 heart attacks, strokes and heart failures in patients over age 65 from the time it was introduced in 1999 until June 2009. The research was funded by the Centers for Medicare & Medicaid Services and by the U.S. Food and Drug Administration.
Since 2007, several studies have questioned the safety of the drug, prompting the FDA to require a black-box warning with all new prescriptions.
Sales of the drug have fallen sharply, but some researchers say failure to completely ban the medication calls into question the FDA’s drug safety process.
By leaving Avandia on the market, “the FDA has basically allowed many thousands of additional patients to be injured or killed with no prospect of unique benefit,” says researcher David Graham, M.D., of the FDA’s Center for Drug Evaluation and Research, who says he is not speaking for the agency.
The drug’s manufacturer, GlaxoSmithKline, says the studies have been inconclusive. The FDA has set a review of the drug’s safety for July 13 and 14.
The JAMA study evaluated 227,571 people on Medicare who took either Avandia (rosiglitazone) or Actos (pioglitazone). It found that, compared with Actos, Avandia had an increased risk of heart failure, stroke and death.
Moreover, Graham says, while Avandia carries increased risks, it is no better than Actos for treating blood sugar problems.
No benefit, increased risk
A separate analysis of 56 clinical trials involving some 35,000 patients—published today in the Archives of Internal Medicine—found that Avandia boosts heart attack, stroke and death by 28 to 39 percent. That study, led by cardiologist Steven Nissen, M.D., of the Cleveland Clinic, is a follow-up to one he conducted in 2007 that found the drug may increase the risk of dying from a heart attack or stroke by as much as 64 percent.
“I said it in 2007. I will say it again. This drug has no unique benefits. It increases risk of very serious consequences, and I believe that it should be removed from the market,” Nissen says.
Nissen calls Graham’s research “a powerful study” and says the two studies, done independently, without funding from any drug companies, have both found the drug carries heart risks.
David Nathan, M.D., professor of medicine at Harvard Medical School, heads a panel of experts convened by the American Diabetes Association to recommend guidelines for treatments of the disease.
He says the group recommended in 2008 that doctors prescribe Actos rather than Avandia when first-line drugs such as metformin didn’t control blood sugar. The American Diabetes Association did not endorse those guidelines.
Because glucose-lowering drugs are aimed primarily at reducing serious diabetes complications to the eyes, kidneys and nerves, drugs like Avandia are “incredibly important,” he explains.
On the other hand, Nathan says, because heart disease is the main killer of diabetics, there’s no reason to use a drug that increases risk of heart problems when other drugs are available.
Although he says the risks of Avandia aren’t absolutely proven, he thinks that the evidence is good enough that he doesn’t prescribe it.
Mary Anne Rhyne, a spokesperson for GlaxoSmithKline, says that previous randomized clinical trials—the gold standard for medical research—found that Avandia does not increase the overall risk of heart attack, stroke or death, and that an analysis of 52 clinical trials conducted by the company found the drug does not interfere with blood flow to the heart.
Neither of the two new studies explained why the drug might cause heart problems.
She says the company looks forward to “participating in a rigorous scientific discussion of the data on the cardiovascular safety of Avandia with the FDA advisory committees.”
Nissen called the upcoming FDA hearing a litmus test for the administration.
“This is a defining moment now for the new leadership for the FDA,” he says. “Will they act decisively? We have people with a public health background now heading up the FDA. Will it be enough to overcome the inertia and get the drug off the market?”
Avandia is reportedly at the center of a furious debate within the FDA, with some officials calling for its removal from the market and others arguing the risks are not proven.
After Nissen’s 2007 study, an FDA advisory panel said that Avandia does raise risks to the heart but voted to keep it on the market. A few months later the agency added a black-box warning about potential heart risks of the drug.
In 2009 about 2 million prescriptions for Avandia costing $663 million were sold in the United States, about a fifth of its peak sales of $3.2 billion in 2006.
Earlier this year, the Senate Committee on Finance reported that GlaxoSmithKline misrepresented findings that the drug may increase cardiovascular risk and “sought ways to downplay findings that a competing drug might reduce cardiovascular risk.”
At the time, the company disagreed with the Senate’s conclusions and pointed out that the FDA had decided the drug should remain on the market based on all the available evidence.
Avandia the new Vioxx?
Graham has been an outspoken critic of the FDA’s process for evaluating drugs’ safety once they are on the market. His estimates of the dangers of the arthritis drug Vioxx were instrumental in its demise. He compares Avandia to Vioxx, the drug that Merck finally pulled from the market after studies showed it increased the risk of heart attack and strokes.
“The people who put Avandia on the market are the people responsible for deciding whether Avandia stays on the market or leaves the market. The country was defenseless against another Vioxx,” Graham says.
Sidney Wolfe, M.D., director of Public Citizen’s Health Research Group, a consumer watchdog group, says the FDA has been “absolutely reckless” in delaying decisive action because of the “overwhelming evidence” that Avandia is dangerous and—importantly—has no benefit over alternative drugs.
Wolfe is on the FDA’s drug safety advisory committee, but he is not going to take part in its upcoming meeting because of Public Citizen’s 2008 petition to the agency to withdraw the drug from the market.
Wolfe and others have also called on the FDA to halt a large-scale clinical trial, known as the TIDE trial, testing the safety of Avandia. The trial, originally requested by the FDA, is set to recruit 16,000 patients at hundreds of sites around the world.
Karen Riley, an FDA spokesperson, says the two new studies published today are “part of a much broader FDA evaluation of the available data” that will be presented at the joint meeting of two FDA advisory committees. Scientists at the meeting will present their evidence and their views on the safety of the drug.
“Drug safety is a core charge for the FDA,” Riley says. Although the agency only approves drugs for the market after it has decided that the benefits of the drug outweigh any risks, safety issues can emerge “because the real world is simply different from the world studied in a clinical trial.”
Riley says the agency will act as quickly as it can after this month’s advisory committee meeting. “More data has been flowing in, and the right way to handle it is to have a vigorous scientific discussion, which we are going to have,” she says.
Nathan of Harvard says after Nissen’s 2007 study in the New England Journal of Medicine and other research called into question Avandia’s safety, many doctors stopped prescribing it. He says he presumes many current Avandia prescriptions are for patients already taking the medication.
“Whether there are new prescriptions being written for that is a real issue,” he says. “It just doesn’t seem sensible to me.… It’s a triumph of advertising over maybe common sense.”
Elizabeth Agnvall is a contributing editor at the AARP Bulletin. Katharine Greider, who lives in New York and writes about health and medicine, contributed to this story.