In the grand scheme of treating diabetes, it might not matter much whether the Food and Drug Administration halts sales of the drug Avandia.
An FDA committee of outside experts met last week to provide advice on whether any regulatory action -- from stronger warnings to removal -- is needed. The FDA has the final say on the committee's recommendations and could decide within weeks.
But doctors already have given their verdict. Avandia prescriptions have plummeted since a study in The New England Journal of Medicine in May 2007 raised concerns about whether the drug increased heart attack risk.
In June 2007, 5.6 million Avandia prescriptions were dispensed in the USA, according to IMS Health, which provides market information to the drug and health care industries. By May 2010, that number had dropped to 1 million.
Mayo Clinic endocrinologist Victor Montori, who wasn't an FDA panelist, says fewer than 10% of U.S. diabetes patients still take the drug. "If the FDA does not do anything, I think the market will continue to shrink," he says.
Strong vote for tight restrictions
The FDA committee gave the agency a lot of wiggle room. Although 20 of the 33 panelists voted to keep the drug on the market, half of those 20 recommended doing so only with tight restrictions.
Such restrictions could lead to a 95% drop in prescriptions by U.S. doctors, estimates Cleveland Clinic cardiologist Steven Nissen, who co-wrote the May 2007 study that launched the public debate. Says Nissen: "It's not like we have a scarcity of options for lowering blood sugar."
And, Montori and other diabetes specialists note, a number of those drugs are cheaper and safer than Avandia and Actos, the only other drug in its class. Although a few panelists at the meeting raised the possibility that Avandia might work better than Actos for some, Montori says there's no evidence to support that notion.
At least one of the 10 advisory panel members who voted to keep Avandia on the market with tight restrictions says he'd actually prefer that the FDA withdraw it. Endocrinologist Clifford Rosen, senior scientist at the Maine Medical Center Research Institute in Scarborough, says the only reason he didn't vote to pull Avandia off the market was because he was "very anxious" he'd be the only one. Panelists press a button to vote; the breakdown is revealed only after all have voted.
"I'm telling you, the drug is done. Nobody should be prescribing it," Rosen said after the meeting. "Anybody who went to or heard this meeting would never prescribe rosiglitazone (the generic name for Avandia) under any circumstances."
Rosen chaired the 2007 advisory committee meeting at which panelists voted 20-3 that Avandia raised heart attack risk but 22-1 that benefits outweighed risks, so sales should continue. Then, the FDA gave panelists only two options: Keep it on the market or not.
Rosen was one of the 22 panelists in 2007 who voted that Avandia should stay, but, he says, he hasn't prescribed it since. He says he and his fellow panelists voted to keep it on the market in 2007 because they didn't know whether Actos might even be riskier. But since then, Rosen says, evidence has accumulated that Actos does not raise heart attack risk as much as Avandia.
Still, both drugs, members of a class called glitazones, are known to raise the risk of fractures, weight gain, fluid retention and heart failure. Neither has ever been on the formulary -- the list of drugs doctors can prescribe -- at the Seattle-based Group Health Cooperative, a non-profit health system that covers 640,000 people.
"There are plenty of other good alternatives," says David McCulloch, a senior diabetes specialist at Group Health who wasn't on the FDA panel.
Problem: Insulin carries a stigma
No endocrinologist will admit to prescribing Avandia, says Harvard endocrinologist David Nathan, director of the General Clinical Research Center and the Diabetes Center at Boston's Massachusetts General Hospital. But endocrinologists treat only 5% or so of diabetes patients, says Nathan, who wasn't a panelist. Primary-care doctors, "who have not been as attuned to the negative press (Avandia) has gotten," see the rest, he says.
Avandia and Actos won FDA approval because clinical trials showed they lowered blood sugar, which was thought to cut heart disease risk. Tight blood sugar control, using multiple drugs, has been shown to reduce the risk of blindness, kidney failure and amputation, long-term complications of diabetes, Nathan says, but some studies show it might increase heart disease risk.
Whether that's a result of the drugs or to the lowered blood sugar itself isn't known, Nathan says, but doctors have backed off advising diabetes patients to go as low as possible.
While they're free to prescribe what they wish, "endocrinologists at the Mayo Clinic have never gotten on board in the prescribing of glitazones," Montori says. The leading endocrinologists at Mayo "have always portrayed glitazones as a potential unnecessary step in the transition of people to insulin."
But insulin carries an undeserved stigma, pushing patients and doctors to use whatever means possible to delay its use, Montori says. "Some people are scared by clinicians who told them, 'if you don't take care of yourself, you're going to end up on insulin.'"
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