FDA panel: Keep Avandia, but add safeguards

Washington -- A pair of votes July 30 by a Food and Drug Administration advisory panel offered mixed recommendations for the agency and signaled caution for physicians who prescribe Avandia (rosiglitazone) to their patients with type 2 diabetes.

The panel examined safety data on the drug and voted by a wide margin, 22-1, to recommend that the agency keep Avandia on the market. But by a similar vote, 20-3, the panelists also recognized the increased risk for heart attacks posed by the drug and urged the agency to consider raising its warning level to black-box status or implementing a patient registration program, panelists said during a news conference.

The agency is not required to follow its advisory panels' recommendations but generally does.

Most primary care physicians treat many patients with type 2 diabetes. More than 14 million people in the U.S. have been diagnosed with the disease, according to National Institutes of Health figures. Those numbers are expected to grow as a result of the pounds being added to the nation's collective midsection.

Citing the vast numbers of people needing treatment, the drug's manufacturer, GlaxoSmithKline, said it welcomed the decision to keep the drug on the market. "The committee recognized the debilitating nature of this disease and the importance of multiple treatment options," Ronald Krall, MD, GSK's chief medical officer, said in comments on the panel's decisions.

The current spotlight on Avandia, which was first sold in 1999, resulted from the publication of a New England Journal of Medicine article in May warning that use of the drug was associated with an increased risk of heart attack compared with placebo. The article prompted the FDA to issue a warning on the use of the drug for people with underlying heart disease or those at high risk of heart attack.

At the time of publication, GSK issued a statement strongly disagreeing with these conclusions, saying they were based on incomplete evidence and methodological limitations.

The article's author, Steven Nissen, MD, chair of the Cleveland Clinic's Dept. of Cardiovascular Medicine, said he was satisfied with several aspects of the advisory committee meeting, including the fact that an FDA analysis of patient data confirmed his earlier findings. He said he also was pleased that "the committee understood the gravity of this type of risk."

But Dr. Nissen said he would have gone further, saying he was "particularly struck" by recommendations to the panel from the FDA's own drug safety personnel that the drug be withdrawn from the market.

Gerald Dal Pan, MD, MHS, director of the FDA's Office of Surveillance and Epidemiology, and David Graham, MD, MPH, associate director for science and medicine in that office, told the panel they thought Avandia should be taken off the market.

But even though the advisory committee thought the drug posed an increased risk, it also pointed to some limitations with the data provided to demonstrate that risk, said Clifford Rosen, MD, chair of the advisory panel and director of the Maine Center for Osteoporosis Research and Education in Bangor.

Arthur Levin, MPH, director of the Center for Medical Consumers, an advocacy group based in New York City, cast the lone negative vote.

Meanwhile, in practices around the country, physicians are now left wondering whether to use Avandia. Dr. Nissen said the panel's votes favoring the continued sale of the drug while acknowledging its dangers represented a paradox.

Views from the field

"The problem is that heart disease is the No. 1 killer of diabetics, comprising anywhere from 60% to 80% of all diabetic deaths," Dr. Nissen said. "So, in the words of David Graham, a diabetes drug that increases the risk of heart disease is unacceptable."

Avandia is not a drug that Dr. Nissen recommends to his patients, and some other physicians say they also avoid it.

"I've never been a fan of this drug," said Benjamin Littenberg, MD, professor of medicine and director of general internal medicine at the University of Vermont in Burlington. "I can't remember ever initiating treatment with it."

Eugenio Cersosimo, MD, PhD, associate professor of medicine at the University of Texas Diabetes Institute in San Antonio, said his institute rarely uses Avandia. It depends more on its counterpart, Actos (pioglitazone), which is a member of the same class and has been the subject of a trial in Europe, where it was found to have some advantages in lowering lipids.

"We have alternatives to [Avandia]," Dr. Littenberg said. "The main reason to use it is in a type 2 diabetic who isn't controlling their sugars with diet, exercise and metformin. And the alternatives in that setting would be the other classes of medicine, or insulin."

Dr. Littenberg urged physicians to consider using insulin earlier in treatment. "We think our patients won't tolerate it well, but they do very well on it, and it is the most efficient and effective way to prevent diabetes' complications."

Larry Deeb, MD, president of medicine and science at the American Diabetes Assn., believes that the debate should shift away from whether to use Avandia and back to lowering the patient's A1c levels to less than 7.

Treatment should focus on "where you are with the patient," he said. Adding Avandia to metformin -- the latter drug is recommended as a first-line treatment in ADA guidelines -- would lower a patient's A1c by only 1%, Dr. Deeb said.

"I would say to the primary care doc: If you choose to use Avandia, do so with clear reason and the understanding of who you are giving it to, why you are giving it to them and what you expect to get out of it," he said.

He also believes that too often, physicians and patients "conspire not to control diabetes." Patients persuade their physicians that they can get their blood sugar levels under control "if I just walk a little more."

Physicians buy this argument, and six months pass, but the patients' blood sugar is still not under control and damage is being done, Dr. Deeb said.