WASHINGTON The government slapped a prominent, though confusing, warning on the popular diabetes drug Avandia on Wednesday telling patients that it may, or may not, increase the risk of heart attacks.
The move is less stringent than steps Canada took last week to restrict the drug's use to hard-to-treat diabetics.
But the U.S. Food and Drug Administration concluded that studies are too contradictory to tell if Avandia really is riskier than other treatments for Type 2 diabetes.
So the FDA described the controversy in a black box on Avandia's label the most severe type of warning the agency can require pending further research. Unlike most black-box warnings that urge strong caution, Avandia's says, "The available data on the risk ... are inconclusive."
"It's still an open question," said Dr. John Jenkins, FDA's drug chief. Still, he said, "We want to make sure health care providers and patients are aware this signal of risk has been identified."
Patients may need a medical dictionary to interpret the new warning. It says Avandia may be associated with "myocardial ischemic events such as angina or myocardial infarction."
In layman's terms, that's chest pain or a heart attack. Manufacturer GlaxoSmithKline PLC is to develop a pamphlet that will come with each bottle putting the warning in easier-to-understand language.
Glaxo also agreed to FDA's demand for a major study directly comparing Avandia and its competitors' heart effects. The study will begin by next November and won't end until 2014, but the FDA will order interim checks to see how patients are faring and if it's possible to settle the issue any sooner.
"It isn't as if we're going to be clueless until 2014," said Dr. Janet Woodcock, FDA's chief medical officer.
For now, Type 2 diabetics who also have heart disease or are at especially high risk for it should talk with their doctor about Avandia's potential heart effects as they decide among treatment options, FDA advised.
In contrast, Canada's drug regulators last week withdrew approval of Avandia as a stand-alone therapy except for patients who can't tolerate older competitors. Health Canada announced that Avandia should be used only in combination with certain other drugs for hard-to-control blood sugar.
Dr. Steven Nissen of the Cleveland Clinic, who first brought the heart attack issue to public attention, said he preferred Canada's approach but that Wednesday's warning is important, if imprecise.
"It is a black-box warning, and no matter what the language says, it's telling you something," Nissen said. "A black-box warning is telling you there's enough evidence here that physicians and patients ought to be concerned."
What should Avandia users do?
"The easy answer is talk to your doctor, but that doesn't help much because the doctors are just as much in the dark as the patient," said Dr. Thomas Pickering, a cardiovascular disease expert at Columbia University Medical Center and an FDA adviser. While he isn't convinced of the heart attack risk, he advises trying other drugs first, and adding Avandia if they're not enough.
It is not the first warning about Avandia's heart effects. In August, the FDA ordered a black-box warning for both Avandia and a competitor, Actos, that they may cause or worsen heart failure, a different cardiac problem.
About 1 million Americans with Type 2 diabetes use Avandia. It helps control blood sugar by increasing the body's sensitivity to insulin.
Diabetics already are at increased risk of heart disease. Type 2 diabetes, the most common form, is linked to obesity, which in turn harms the heart. Plus, high blood sugar over time damages blood vessels. Lowering glucose prevents many diabetes complications, such as blindness and kidney failure.
The hope is that intensive treatment also will lower the risk of a heart attack.
But on Wednesday, the FDA also said Avandia's competitors must change their own labels to say none has been proven to reduce diabetics' risk of heart disease. That includes the treatment mainstay metformin, a family of medicines called sulfonylureas, and Actos.
The Avandia question, however, is whether it might actually increase heart attacks.
Last May, Nissen and colleagues published an analysis that found Avandia users had a 43 percent higher risk of heart attack than other diabetics. The analysis added 42 different studies that included 14,000 patients, most that compared Avandia users with diabetics given a dummy pill and tracked them for six months.
But three other studies together tracked the same number of patients for a few years and neither confirmed nor refuted the heart attack risk, FDA found. Those studies mostly compared Avandia to other diabetes medications, and some suggested Avandia might even help diabetics live longer, Jenkins said.Last summer, FDA's independent scientific advisers ruled the heart risk probably was real but that Avandia should stay on the market with warnings. In further debate, FDA's own employees sharply split on how to address Avandia, although Woodcock said a majority wanted it kept on the market.
On the Net: Food and Drug Administration: www.fda.gov/