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For Diabetes Drug Avandia, Bad News Continues

For Diabetes Drug Avandia, Bad News Continues: Two new studies link the drug to increased heart risks just weeks before the FDA will consider whether it should remain on the market. [Los Angeles Times]

From Los Angeles Times (CA) (June 28, 2010)

June 28--The diabetes drug Avandia, once the world’s top-selling diabetes medication, took two more hits Monday with one new study linking it to an increased risk of heart attacks and a separate study linking it to an increased risk of heart failure and stroke. The research comes only weeks before an upcoming federal hearing to reconsider its fate.

The drug, also known by its generic name rosiglitazone, was approved in 1999 to help people with Type 2 diabetes control their blood sugar. At the time, it was considered a safer alternative than existing diabetes drugs used instead of insulin. Soon after approval, however, the drug was linked to an increased risk of heart failure and bone fractures; worries about the drug’s safety increased in 2007 when a meta-analysis -- a pooling of previous studies -- concluded that the drug increased the risk of heart attack.

One of the studies released Monday, a larger meta-analysis, found Avandia raised the risk of heart attacks by 28% to 39% as compared with other diabetes medications. The study was published online in the Archives of Internal Medicine.

The other new study, an observational study of Medicare recipients published online in the Journal of the American Medical Assn., found Avandia increased the risk of stroke by 27%, heart failure by 25% and death from any cause by 13% compared with another popular diabetes drug, Actos.

"We have two studies done by independent groups, published in very responsible journals using different approaches coming to the same conclusion," said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation and the lead author of the Archives study and the 2007 analysis. "It’s everything we know about this drug during its very sad and unfortunate history."

Both studies are scheduled for print publication in July. They were released early in advance of a Food and Drug Administration hearing on July 13 and 14 that will consider whether Avandia should remain on the market.

The drug’s manufacturer, GlaxoSmithKline, defended Avandia on Monday, saying that the new studies stand in contrast to a randomized clinical trial of 4,447 patients conducted by Glaxo. That study found rates of hospitalization and deaths from cardiovascular events were similar among Avandia patients and those taking other diabetes medications, such as metformin and surfonylurea.

The study, called RECORD, for Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes, was published last year in the Lancet.

Glaxo officials said in a statement that data from RECORD and five other controlled, clinical trials provided evidence of the drug’s safety.

"Taken together, these trials show that Avandia does not increase the overall risk of heart attack, stroke or death," Glaxo officials said. The company has conducted its own meta-analysis of 52 clinical trials "and it does not show an increase in myocardial ischemia."

On its website, the FDA notes that the RECORD data is the only new information on Avandia (another randomized trial is ongoing) and that its findings will be at the core of the evaluation next month. It’s not known how the two new studies will influence the committee.

However, Nissen said his review is the most comprehensive to date. He and colleagues at the Cleveland Clinic Foundation analyzed 56 studies, from GlaxoSmithKline and other researchers, with a total of 35,531 patients who received either Avandia or another diabetes medication for comparison. Although they found no differences in cardiovascular death rates between the two groups, they did find the increased risk of heart attack among Avandia patients.

"If you have a drug to increase the rate of heart attack by a third, it is a public health hazard that is enormous," Nissen said. "This drug has no redeeming features, no unique benefits."

The other study, published in JAMA, analyzed data from 227,571 Medicare beneficiaries who started treatment with Avandia or Actos, which is also known by its generic name pioglitazone, between July 2006 and June 2009. That study found no difference in the risk of heart attacks but did find increased risk of stroke, heart failure and death by any means, according to the lead author, Dr. David J. Graham, epidemiologist and associate director of the FDA’s Center for Drug Evaluation and Research, and co-authors from Stanford University and the Centers for Medicare & Medicaid Services.

The discrepancy in heart attack rates in the two studies can likely be explained by patient age, Nissen said. The average age of patients in his study was 55 compared with 74 in the JAMA study. If those patients died of a heart attack before reaching the hospital, as is more common among the elderly, their deaths would not show up in the statistical analysis.

The major value of the JAMA study, is that it compared Avandia and Actos, said Dr. David N. Juurlink, an internist and chief of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto who wrote an editorial accompanying the study. Avandia and Actos both belong to a class of drugs called thiazolidinediones.

"What it suggests is that Avandia is more likely than Actos to cause a variety of safety concerns," Juurlink said. "Why would you want to be on [Avandia] when there is a safer alternative?"

The mechanisms by which Avandia could increase cardiovascular harm are not clear, Nissen said. The drug might increase low-density lipoprotein cholesterol or, in people with a genetic predisposition, increase production of an enzyme that ruptures plaque in arteries.

The American Diabetes Assn. has recommended doctors stop prescribing Avandia. In February, leaders of the U.S. Senate Committee on Finance released a report calling for Avandia’s removal and charging the FDA with knowing about the drug’s link to heightened cardiovascular risks well before the link became known publicly.

The FDA has advised health professionals to adhere to information on the drug label, which includes warnings about heart failure and a possible increased risk of heart attack. According to the FDA, patients should continue taking Avandia unless told by their healthcare professional to stop.

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Posted: June 2010