U.S. studies conflict on Glaxo diabetes drug risk

WASHINGTON (Reuters) - Two studies reported serious heart risks with GlaxoSmithKline Plc's diabetes pill Avandia while a third contradicted those findings, adding to a debate over whether the drug should stay on the market.

The conflicting results were released on Monday, two weeks before an advisory panel meets to sort through a vast amount of data and help decide Avandia's future. The medicine was Glaxo's second-biggest drug but is much smaller after a safety controversy erupted three years ago.

One analysis of 56 clinical trials found Avandia increased the chances of a heart attack by 28 percent to 39 percent, researchers at the Cleveland Clinic in Ohio said in an update to a 2007 study that sparked debate about the drug.

Dr. Steven Nissen, the lead author and an outspoken Avandia critic, said the results from more than 35,000 patients gave a more complete picture that reinforced his earlier concerns.

"A drug that increases the risk of heart attack by a third or more in diabetics represents a huge public health burden," Nissen, the Cleveland Clinic's head of cardiology, said in an interview. He said the drug should come off the market.

U.S. Democratic Representative Rosa DeLauro said the newly published data along with earlier findings "appear to confirm that Avandia is dangerous and should be pulled from the market.

But a study released at an American Diabetes Association meeting in Orlando, Florida, found diabetics taking Avandia were 28 percent less likely to die or have a heart attack or stroke compared with people who did not take a drug in the same class.

The National Institutes of Health-funded analysis looked at a clinical trial of more than 2,300 diabetics with heart disease. Glaxo provided some funding.

KEEPING OPTIONS

The lead researcher, Sheryl Kelsey of the University of Pittsburgh, said Avandia appears safe in high-risk diabetics whose other risk factors, such as smoking and high blood pressure, are under control.

Kelsey said many of her colleagues support keeping Avandia available. "There are people who want to have the choice of diabetes drugs be broad, and Avandia should be an option," she said.

Glaxo shares fell 0.9 percent to close at $34.30 on the New York Stock Exchange. The third study which showed benefits from Avandia was released after U.S. markets closed.

In another study released on Monday, government researchers said an analysis of more than 227,000 U.S. Medicare patients found Avandia was more dangerous to the heart than a rival pill, Takeda Pharmaceutical Co Ltd's Actos.

Those findings, reported earlier this month by Reuters and others, were published online by the Journal of the American Medical Association. The lead researcher is Food and Drug Administration reviewer David Graham, who has argued for years that Avandia is too risky.

Top FDA officials have disagreed and Glaxo has vigorously defended the drug, known generically as rosiglitazone.

In February, the FDA said it was again reviewing Avandia's risks. The new studies are "important contributions to the discussion of Avandia's safety," FDA Deputy Commissioner Joshua Sharfstein said in an interview.

The agency and the advisory panel that meets in July will consider those findings plus others, including FDA analyses not yet made public, he said.

The panel could urge keeping the drug on the market with a warning, or it could suggest prescribing limits or a ban on future sales. The FDA usually follows panel recommendations.

The FDA, which approved Avandia 11 years ago, will "review all the available evidence," Sharfstein said.

In the meantime, the agency has advised patients to continue using Avandia as directed. The current FDA-approved warning on Avandia says heart attack data are "inconclusive."

Avandia's use fell sharply after Nissen's first study, but it remains widely prescribed with sales of $1.2 billion globally in 2009. For drug giant Glaxo, it is now a small product. U.S. sales for 2009 -- $663 million -- made up 1.5 percent of the company's $44.25 billion in total sales.

DAMAGE DONE

The new studies could further depress use, but "the damage has really been done," Morningstar analyst Damien Conover said. The bigger concern for Glaxo is liability lawsuits if the drug comes off the market, which Conover said was unlikely.

"It's hard for me to see anything incrementally that's come out since the FDA has already taken a look at this issue" to lead to a withdrawal, Conover said.

Capitol Street analyst Ipsita Smolinski estimated a 30 percent to 40 percent chance the FDA panel would urge severe limits or withdrawal, depending on who sits on the committee.

Glaxo said six randomized clinical trials, the gold standard for medical studies, showed Avandia did not increase the overall risk of heart attack, stroke or death.

The studies from Nissen and Graham are among the largest for Avandia, but they rely on a combination of multiple trials or past Medicare claims. Such studies are considered less reliable than randomized clinical trials.

In a commentary discussing Graham's findings, Dr. David Juurlink of the Institute for Clinical Evaluative Sciences in Toronto argued for erring on the side of public safety.

"Accumulating concerns about (Avandia) make it difficult to advance a cogent argument why, exactly, a patient might want to receive the drug," Juurlink wrote.

Many of the 23 million U.S. diabetics take medicines to lower blood sugar. The goal is to prevent disease complications such as blindness, amputations and heart disease, the leading killer of people with diabetes.

But critics say Avandia seems to contribute to heart damage. Nissen's study, published by the Archives of Internal Medicine, estimated one more heart attack would occur for every 37 to 52 people who took the drug for five years.

Graham's analysis, done with researchers at the FDA and the Centers for Medicare & Medicaid Services, found a 27 percent higher stroke risk for Avandia over Actos, a 25 percent greater risk of heart failure and a 14 percent higher chance of dying.

"In older Americans with diabetes, taking Avandia is detrimental to your health" and patients "are far better off taking (Actos)," Graham said in an interview.

Both Graham and Nissen have been asked to speak to the FDA panel, Sharfstein said.

Diabetics have many alternatives as 12 classes of drugs are approved to lower blood sugar, Nissen said. They include older generic drugs such as metformin and newer medicines such as Merck & Co Inc's Januvia and AstraZeneca Plc and Bristol-Myers Squibb Co's Onglyza.

(Reporting by Lisa Richwine, Susan Heavey, Maggie Fox and Julie Steenhuysen; editing by Lisa Von Ahn and Matthew Lewis)