Avandia safety under fire again

The safety of Avandia (rosiglitazone, GlaxoSmithKline) is being questioned again, this time by the U.S. Senate. A report issued by the Senate Finance Committee earlier this year noted that Avandia is associated with 83,000 excess heart attacks occurring between 1999 and 2007. The report also noted that GSK has been aware of the cardiac risks of the drug for several years but has attempted to keep the risks out of the public eye. The drugmaker disputed the committee's conclusions.

"Americans have a right to know there are serious health risks associated with Avandia and GlaxoSmithKline had a responsibility to tell them," said committee chair Max Baucus (D-Mont.). The ranking minority member, Sen. Chuck Grassley (R-Iowa), concurred with Baucus' evaluation.

The committee also revealed that at least two FDA safety investigators recommended that Avandia be taken off the market because of the risk of cardiac events. Other FDA officials called the cardiac safety data contradictory and recommended that the agent remain on the market. The agency last reviewed Avandia safety data in 2007 after Cleveland Clinic cardiologist Steven Nissen, MD, published a meta-analysis concluding that the drug increases the risk of myocardial infarction by 43%. The Senate report noted that internal analyses at GSK and FDA reached similar conclusions.

"We are encouraging pharmacists and patients to have a discussion about diabetes treatment and to talk with the prescriber," said Marcie Bough, director of federal regulatory affairs, American Pharmacists Association. "We hope the July meeting may yield more data and a more studied discussion of the safety issues. The one thing patients should not do is stop taking the drug without telling anyone."

TIDE trial discussion in July

FDA is also undertaking a study with the Institute of Medicine to determine the technical and ethical issues associated with postmarket drug safety. In May 2008, FDA required that a head-to-head study comparing Avandia to pioglitazone (Actos, Takeda) be conducted by GlaxoSmithKline to evaluate the cardiovascular safety of these two antidiabetic agents. The study, titled Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE), has been called into question by scientists because of ethical concerns.

FDA Commissioner Margaret Hamburg, MD, explained in a letter to Sen. Grassley dated March 30, 2010, that the TIDE trial will be discussed in July at the meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees.

Black-box issues

Cardiac events are a known complication of the thiazolidinedione (TZD) class of oral antidiabetic agents. Actos carries a black-box warning for congestive heart failure, while Avandia carries a warning for congestive heart failure and myocardial ischemia. The American Diabetes Association (ADA) has not advised patients to switch to Actos, but the group has dropped Avandia from treatment guidelines for type 2 diabetes. ADA now lists Actos as the appropriate choice for second-line treatment if lifestyle changes and metformin (Glucophage, Bristol-Myers Squibb) fail to adequately control blood glucose levels.

The cardiovascular risks of rosiglitazone were evaluated in a prospective randomized controlled trial known as the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial. Final results suggested a doubling in the risk for heart failure with rosiglitazone and no overall increase in cardiovascular death. But the open-label study was designed to compare rosiglitazone with other regimens and was underpowered to assess cardiovascular effects. The trial was also weakened by poor medication adherence, a high crossover rate between arms, and an imbalance in the use of statins and other medications that appeared to favor the rosiglitazone arm.

"First and foremost, you want patients to be entirely comfortable with the drugs they are on," said Richard Bergenstal, MD, ADA president for medicine and science. "If your patients are on a TZD, assume they have a question and bring up the issue yourself. As it stands, pioglitazone has one black-box warning and rosiglitazone has two. I'd like to hope that FDA clarifies rosiglitazone's indeterminate status."

Dr. Bergenstal said he is not overly concerned by the apparent split in the FDA ranks over the safety of Avandia.

"I have a feeling that it happens more often than we have been aware of," he said. "The real problem here is inadequate data, which leads to varying interpretations and opinions. If we need more data, which we do, the FDA needs to insist on cooperation from all the parties."