Diabetes Drug Found to Raise Heart Attack Risk

A new study reported that GlaxoSmithKline's drug Avandia, used to treat Type 2 diabetes, increased heart attack risk by 43 percent. (By Jb Reed -- Bloomberg News)

A drug commonly used to control diabetes increases the risk of heart attacks and possibly death, researchers reported yesterday in the latest episode to raise safety concerns about a widely prescribed drug.

The drug, Avandia, which about 1 million Americans take to keep their blood sugar at safe levels, boosts the risk of a heart attack by 43 percent and may increase the risk of dying from a heart attack or stroke by 64 percent, the analysis found.

"This is very concerning," said Steven E. Nissen of the Cleveland Clinic, who conducted the analysis with colleague Kathy Wolski. The report was released early by the New England Journal of Medicine because of the public health implications. "When you have a drug widely used in a population with a high inherent rate of heart disease, it's very, very concerning."

Nissen and others said patients taking the drug should immediately consult with their doctors about whether they should switch to another medication.

"There is no need to panic," said M. Sue Kirkman of the American Diabetes Association, which issued a statement with the American Heart Association and American College of Cardiology expressing concern about the findings. "But patients need to talk with their physicians to decide what's the best course for them."

GlaxoSmithKline, which makes Avandia, defended the drug's safety, saying that the analysis had fundamental limitations and that other more reliable large studies have found no evidence of increased risk.

"We are confident in the benefit-risk profile for Avandia," said Ronald Krall, the company's chief medical officer. "It is an important treatment for patients with Type 2 diabetes."

The report prompted the Food and Drug Administration to issue a safety alert about Avandia, but others said the new data called for adding warnings to the drug's label or possibly pulling it off the market.

"Unless the FDA has some kind of data that provides a different picture, then some sort of action is warranted," said Bruce M. Psaty of the University of Washington, who co-wrote a commentary accompanying the study. "I just don't see a reason to have this drug on the market."

The commentary said Avandia, whose chemical name is rosiglitazone, "represents a major failure" of the drug safety system.

In their analysis, Nissen and Wolski pooled data from 42 studies that have been conducted on the drug. Among more than 27,843 patients in the relatively brief studies, 86 of those taking Avandia had a heart attack, compared with 72 of those not taking the drug. Thirty-nine patients taking the drug died of cardiovascular causes, compared with 22 not taking the drug.

In their paper, which will be published in the June 14 issue of the journal, they calculated that those numbers translated into a statistically significant 43 percent increased risk of heart attack and a 64 percent increased risk of death from any form of cardiovascular disease, a rate that fell just shy of being statistically significant.

Nissen said the findings mean that over a seven-year period, the risk of a diabetic with no known heart disease having a first heart attack while taking the drug would increase from about 20 percent to nearly 29 percent.

Several lawmakers expressed alarm about the report. Rep. Henry A. Waxman (D-Calif.) announced plans to hold a hearing June 6 on the FDA's role in evaluating the drug. Sens. Max Baucus (D-Mont.) and Charles E. Grassley (R-Iowa) sent letters demanding that the FDA explain its handling of the case and say whether Glaxo or the agency withheld concerns from the public.

"Both the drug company and the FDA have some major explaining to do about what they knew about Avandia, when they knew it, and why they didn't take immediate action to protect patients," Baucus said.

During a hastily convened telephone briefing with reporters, the FDA defended its handling of Avandia. The agency acknowledged it had received a similar analysis from Glaxo in August that found a similar, though somewhat smaller, increase in risk, but said it also had conflicting data, making it premature to take any action.

"At this point we have not reached a definitive conclusion," said the FDA's Robert J. Meyer. The agency will probably convene a panel to advise on the issue, he said.

The findings prompted new calls to overhaul the drug safety system, which has come under intense criticism because of a series of revelations about the dangers of widely used drugs, most notably the arthritis drug Vioxx, which was taken off the market in 2004.

"Here we have yet another example of a very commonly used drug taken by millions and millions of patients that has important safety concerns that the FDA has missed for years and years and years," said Jerome L. Avorn of Harvard Medical School. "How many of these do we really need to happen before we step back and do something?"

The concerns come as Congress is considering legislation that would give the FDA new powers to monitor drug safety. Avorn and others called for empowering the agency to require pharmaceutical companies to conduct follow-up research on drugs, especially those that are approved quickly.

"Large long-term trials evaluating the risks and benefits of drugs like this need to be done as soon as possible. Here we have a case where we're eight years out and we're just now finding out about this," Psaty said.

Avandia was approved in 1999 for patients with Type 2 diabetes, the most common form. About 18 million Americans have that type of diabetes, which causes blood sugar to rise to dangerous levels, increasing the risk of a host of complications, including heart attack. Diabetics face about double the usual risk of a heart attack. The drug helps control blood sugar levels by increasing the effectiveness of the insulin the body produces.

Glaxo officials acknowledged that they had found a somewhat smaller increased risk in a similar "meta-analysis," but said a number of other studies found no such increase, including large ongoing studies being monitored by independent safety experts.

"We place great weight on long-term observational studies," Krall said. "Those studies have not shown evidence of an increased risk."