June 28, 2010 -- People who take the widely used diabetes drug Avandia may be putting themselves at higher risk of developing fatal heart problems, according to two large studies published today in the Journal of the American Medical Association.
The first study analyzed 56 studies totalling more than 35,000 patients that compared Avandia to other drugs used to lower blood sugar in patients with diabetes. Patients taking Avandia were 33 percent more likely to have a heart attack compared to those on other treatments, according to the study.
The second study, by Dr. David Graham, associate director of the Food and Drug Administration, analyzed data collected from more than 220,000 elderly patients in a Medicare health insurance program who either took Avandia or its equivalent class drug Actos. While the study found an increased risk of heart failure, stroke and death among patients taking Avandia compared to those taking Actos, there was no difference in risk of heart attack among those taking Avandia and Actos.
"There is no reason for this drug to be given to patients," said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, and author of the first study.
Watch ABC News' senior health and medical editor Dr. Richard Besser's report on Avandia tonight at 6:30 p.m. ET on "World News With Diane Sawyer"
These studies are not the first to question Avandia's safety. GlaxoSmithKline first reported the results of its review -- which found an increased risk of heart attacks in Avandia patients -- to the FDA in 2005, but neither the company nor the federal agency issued a public warning at the time.
A 2007 study conducted by Nissen first raised public concern about Avandia's cardiovascular effects. The FDA decided in November 2007 to leave the drug on the market, with the addition of a black box warning of the risk of heart attack.
Since then, the popular diabetes drug lost more than half of its sales, although it still generated more than $1 billion in revenue last year alone.
Nissen said his latest study, the largest to date analyzing the potential adverse effects of Avandia, confirmed his previous findings. Still, dueling reports have gone back and forth on whether the cardiovascular risk associated with Avandia is real.
Weighing In on the Risks
These studies come just weeks before a July 13 FDA advisory committee panel to review the safety of Avandia, developed by GlaxoSmithKline. The panel's recommendations could include keeping the drug on the market, calling for further restrictions or pulling it altogether.
The consumer watchdog group Public Citizen took the new analyses as an opportunity to push for the FDA to stop marketing Avandia.
"Every month that the FDA fails to get the drug withdrawn from the market means that an additional 150,000 to 200,000 prescriptions will be filled in this country, needlessly exposing people to the increased risk of stroke, heart failure and heart attacks," Dr. Sidney M. Wolfe, director of Public Citizen's health research group, said in an e-mail.
According to Nissen, the challenge to pull the drug off the market lies in bridging the so-called internal conflict between the FDA's drug approval committee, and the committee that reviews safety. The authority rests with those who approve medications, said Nissen.
"Historically, it's hard to get drugs off the market once it's been successfully marketed," said Nissen.
People with diabetes have a higher than average risk of having a heart attack or stroke, more than twice as often as people without diabetes, according to the American Diabetes Association.
"The whole purpose of treating diabetes in the first place is to prevent the complications of diabetes -- chief of which is heart disease, stroke, and premature mortality," said Graham. "What sense does it make to give a drug that increases all three?"
And many experts agree, saying they stopped prescribing Avandia to patients when reports were first released about its potential harm.
"I have not used Avandia for years," said Dr. John Messmer, associate professor of family and community medicine at Pennsylvania State College of Medicine. "I noted that too many of my patients retained fluid, became hypertensive and even had worsening heart failure, so I discontinued using it even before the warnings came out."
These Studies Don't Say Much, Some Experts Said
Some experts said these reports do not show enough evidence to pull the drug from the market.
Dr. Christopher Cannon, cardiologist at Brigham and Women's Hospital in Boston, said both of the studies drew opposite conclusions. The first study found a higher risk of heart attacks compared to other drugs, while the second one, which compared to Avandia to Actos, did not.
"This raises questions on what to believe, and thus more randomized data would be the key here," said Cannon.
Besides the actual data, some experts said the premise of these studies feeds into a long-standing motivation by the authors to persuade the FDA to pull Avandia from the market.
"I feel the publication and presentation of these studies were orchestrated for political motives, not for scientific reasons," said Dr. Joel Zonszein, director of the clinical diabetes center at Montefiore Medical Center in New York. "These two newer reports will undoubtedly contribute to the political football played by the FDA, even when they did not contribute to relevant new data."
According to the Dr. Domenic Sica, chairman of clinical pharmacology and hypertension at Virgina Commonwealth University in Richmond, many studies released on Avandia are not as strong as the study authors typically present.
"Sometimes the motivation for attacking a drug is personal, and it is often quite difficult in separating out the really bad with a drug from the perception of bad on the part of an author," said Sica. "Do I think that this drug should be pulled from the market? No."
According to a statement released by GlaxoSmithKline, the company also reviewed the updated studies on Avandia and said that stronger studies, such as the randomized control trial Record, do not find an increased heart attack risk with the drug.
"GSK also has updated its prior meta-analysis to include data from 52 clinical trials, and it does not show an increase in [angina]," GlaxoSmithKline wrote in a statement. "Review of these studies with tighter confidence intervals have risk ratios that are very close to one, indicating no difference in the risk of [heart attack] between rosiglitazone [Avandia] and pioglitazone [Actos]."
Call for Action
Doctors prescribe Avandia to lower blood sugar in diabetes patients, but there are more than a dozen classes of diabetes treatments available that are now used as alternatives to Avandia, many experts said.
"Almost everyone can see the clear difference between public health and public endangerment," said Wolfe.
According to Nissen, other potentially safer alternatives to Avandia -- such as its class equivalent Actos -- suggest Avandia is not a necessary medication for a majority of diabetes patients. There are no unique benefits to Avandia, he said.
"If [Avandia] was the only drug in the class, [we] could have an argument to keep it around," said Nissen.
Nissen said a 2007 presentation to the FDA advisory board by Graham estimated that more than 200,000 patients died from taking Avandia since possible cardiovascular effects of the drug were first reported.
"I think the conclusion is pretty clear," said Nissen. "Now let's get on with it. Get this drug off the market."
Dr. Steve Nissen is a paid consultant for pharmaceutical companies, including GlaxoSmithKline, and Takeda Pharmaceuticals. Nissen said he donates all compensation to various organizations. Dr. Domenic Sica is a consultant and investigator for Takeda in the area of hypertension.