Diabetes drug Avandia harms heart, reports say

Hundreds of people taking Avandia, a diabetes medicine, needlessly experience heart attacks and heart failure each month, according to government reports that recommend the drug be removed from the market.

The reports say that if every diabetic now taking Avandia were given instead a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart. Avandia, intended to treat Type 2 diabetes, is known as rosiglitazone and was linked to 304 deaths during the third quarter of 2009.

"Rosiglitazone should be removed from the market," one of the reports, written by Dr. David Graham and Dr. Kate Gelperin of the Food and Drug Administration (FDA), concludes. Both recommended that Avandia be withdrawn.

The internal FDA reports are part of a debate within the agency over what to do about Avandia, manufactured by GlaxoSmithKline. Some agency officials want the drug withdrawn because, they say, there is a safer alternative; others insist that studies of the drug provide contradictory information and that Avandia should continue to be an option for doctors and patients. GlaxoSmithKline said it had studied Avandia extensively and "scientific evidence simply does not establish that Avandia increases" the risk of heart attacks.

The battle has been brewing for years but was brought to a head by a fierce disagreement over a new clinical trial and a Senate investigation that concluded that GlaxoSmithKline should have warned patients earlier of the drug's potential risks.

Avandia was once one of the biggest-selling drugs in the world. Driven in part by a multimillion-dollar advertising campaign, sales were $3.2 billion in 2006. But a 2007 study by a Cleveland Clinic cardiologist suggesting that the drug harmed the heart prompted the FDA to issue a warning, and sales plunged.

A committee of independent experts found in 2007 that Avandia might increase the risk of heart attack but recommended that it remain on the market, and an FDA oversight board voted 8-7 to accept that advice.

Hundreds of thousands still take the medicine, although some top endocrinologists say they have sworn off the drug.

"Conflicting opinions"

Since 2007, more studies have been done. In a December 2009 internal memorandum, Dr. Janet Woodcock, director of the FDA's drug center, wrote that "there are multiple conflicting opinions" about Avandia within the agency, and she ordered officials to assemble another advisory committee, expected this summer, to reconsider whether the drug should be sold.

"I await the recommendations of the advisory committee," the agency's commissioner, Dr. Margaret Hamburg, said late Friday. "Meanwhile, I am reviewing the inquiry made by Senators Baucus and Grassley, and I am reaching out to ensure that I have a complete understanding and awareness of all of the data and issues involved."

The bipartisan, multiyear Senate investigation, whose results were released Saturday, criticizes GlaxoSmithKline, saying it failed to warn patients years earlier that Avandia was potentially deadly.

"Instead, GSK executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk," concludes the report, overseen by Sen. Max Baucus, D-Mont., and Sen. Charles Grassley, R-Iowa.

Baucus said of the report: "Patients trust drug companies with their health and their lives, and GlaxoSmithKline abused that trust."

In response, GlaxoSmithKline said it disagreed with the Senate investigation's conclusions. The company said it could not comment on internal FDA documents but that "the official ruling from FDA is that Avandia remain on the market."

After the controversy, agency officials ordered GlaxoSmithKline to undertake a study comparing how many heart attacks, strokes and heart-related deaths occur among patients given Avandia, Actos or a placebo. Studies suggest that Actos, made by Takeda, lowers blood sugar, as well as Avandia, but without hurting the heart as much.

Graham and Gelperin, the FDA doctors, work in the FDA's office of surveillance and epidemiology. They argued in two separate internal reports that the new GlaxoSmithKline study, TIDE, is "unethical and exploitative" because patients given Avandia face far greater risks than those given Actos, with no promise of any additional benefit.

Indeed, the trial may include patients who have had heart attacks or chest pains even though some foreign drug authorities have warned against Avandia's use by precisely such patients, the reports note.

Concerns overruled

These concerns were overruled, and GlaxoSmithKline is enrolling patients in the TIDE trial. The trial is not expected to be completed until 2020. The company's patent on Avandia expires in 2012, when generic versions will probably swallow most remaining profits.

The Senate investigation — the result of years of digging through more than 250,000 internal company documents — concludes that GlaxoSmithKline, and by extension the FDA, delayed far too long in this process.