Two more studies published in yet another prominent medical journal have raised questions about the safety of Avandia, a once-popular diabetes medicine.
One study found that Avandia, made by GlaxoSmithKline, doubled the risks of heart failure and raised the risks of heart attack by 42 percent. A second study found that Actos, a similar drug made by Takeda, actually lowered the risks of heart attacks, strokes and death but, like Avandia, also raised risks of heart failure.
Taken together, some of the authors said, the two studies in The Journal of the American Medical Association confirm what doctors and patients using Avandia have already done in great numbers, that is, switch to another drug. Sales of Avandia have plunged.
GlaxoSmithKline said in a written statement that the studies were flawed and "offered no new information on the safety of Avandia." The company "continues to support Avandia as safe and effective when used appropriately," the statement said.
In July, a federal advisory panel voted overwhelmingly that Avandia should remain on the market even though it raised the risks of heart attacks. In June, the Food and Drug Administration said it would place its strictest warnings on the labels of both Avandia and Actos because of heart failure risks.
Riven by internal disagreements, the drug agency is still pondering further regulatory actions regarding Avandia. Some in the agency say that the drug should be withdrawn, while others say that all diabetes drugs have risks and that doctors need a variety of options.
The controversy began in May when The New England Journal of Medicine published a combined analysis of more than 40 studies of Avandia that found that it significantly raised the risks of heart attacks. The study attracted wide attention, but it was also criticized by the company and some on Capitol Hill as flawed.
In the study's aftermath, the drug agency said that it had been told in 2005 of a similar study conducted by GlaxoSmithKline that came to a similar conclusion. Critics denounced the agency's delay in alerting patients.
Dr. Richard Hellman, president of the American Association of Clinical Endocrinologists, said that the new studies were "more evidence that we should have a very high level of caution" regarding the use of Avandia. The drug agency should further strengthen the warnings on Avandia's label to make it clear that the drug should be used very sparingly.
In the first study, researchers from Wake Forest University did yet another combined analysis of Avandia studies, this time limiting themselves to four long-term studies. The authors' hope was that, by focusing on such a select set, their analysis would avoid some of the limitations of the May analysis.
The redo came to a conclusion almost identical to that of the study published in May. Dr. Sonal Singh, an assistant professor of internal medicine at the Wake Forest School of Medicine and a co-author of the study, said the drug agency should consider withdrawing Avandia from the market.
In addition to its deleterious effects on the heart, Avandia can cause blindness, and it doubles the risks of bone fractures in women, Dr. Singh said in an interview.
"If you use Avandia to treat patients with Type 2 diabetes," he said, "their chance of getting heart failure due to Avandia is one in 30 and their risk of getting a heart attack is one in 220. All due to the drug."
Dr. Singh added, "There are older and cheaper drugs that are far better to treat diabetes."
In the second study, researchers at the Cleveland Clinic combined data from 19 trials of Actos and found that the drug seemed to lower the risks of heart attack, stroke and death by about 20 percent. The study confirmed that Actos increased the risks of heart failure, but this problem is mostly reversible.
"I think this shows that these drugs aren't the same," said Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic.
Dr. Lincoff said that Actos not only appeared to be safer than Avandia, but also offered some protection to the heart. Most diabetics die of heart disease.
In an accompanying editorial, two doctors from Brigham and Women's Hospital in Boston wrote that Avandia would probably not have been approved in 1999 had its heart risks been known.
In an interview, Dr. Daniel H. Solomon, a co-author of the editorial, called Avandia "a drug of last resort."
Dr. Solomon wrote that the Avandia situation should be used to improve the nation's drug-safety system. Among his proposals is that when several drugs are available to treat a condition, new drugs must prove that they improve or extend people's lives before they are approved. Now, many drugs are approved only after they improve laboratory results, like blood sugar or cholesterol levels.