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 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 sulfonylurea.
The study, called RECORD, for Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes, was published last year in the Lancet.
Moreover, a study released Monday at the American Diabetes Assn. meeting in Orlando, Fla., found that Avandia did not increase cardiovascular events or deaths compared with other anti-diabetes drugs. The study was a post-hoc analysis — a review of a completed study — of patients with both Type 2 diabetes and heart disease.
Researchers reviewed almost five years of data comparing 992 people who had taken Avandia at some point during the study to 1,199 patients who had taken another anti-diabetes drug that was not in the same class of medication as Avandia. The study showed that people on Avandia had fewer heart attacks, strokes and deaths, but more bone fractures, than people taking other medications.
"The uncertainty that has plagued rosiglitazone from previous clinical trial data remains difficult to reconcile," said the lead author of the study, Dr. Richard G. Bach, of the Washington University School of Medicine in St. Louis.
On its website, the FDA notes that the RECORD data are the only new information on Avandia (another randomized trial is ongoing) and that the findings will be at the core of the evaluation next month.
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.
The discrepancy in heart attack rates in the two studies can probably 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.
An American Diabetes Assn. consensus panel has recommended that 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.