New pill increases risk of strokes

The FDA notified the company Tuesday that the drug was 'approvable.'
WASHINGTON POST
WASHINGTON -- A diabetes medicine poised to win Food and Drug Administration approval sharply increases the risk of heart problems, strokes and death, researchers reported Thursday in an analysis that raises pointed new questions about the agency's handling of drug safety issues.
The drug, Pargluva, the first in what had been considered a promising new class of diabetes drugs, more than doubles the risk for life-threatening cardiovascular complications, the researchers concluded after analyzing the studies the drug's maker presented in its application for approval. Based on the findings, the researchers urged the FDA to withhold approval until additional research can be conducted on the safety questions.
"I do not think it's wise to approve the drug or see the drug marketed until there's a dedicated cardiovascular safety trial," said Steven Nissen, of the Cleveland Clinic Foundation, who led the analysis. "We have to put safety first."
Study released
The Journal of the American Medical Association released the study online Thursday, five weeks ahead of its Nov. 23 publication, because of the public health implications.
The FDA on Tuesday notified the company that the drug was "approvable" pending additional information about the drug's safety, but it did not specifically request a new study designed to examine the risk of cardiovascular problems.
The critique comes as the agency is struggling to restore its credibility in the wake of a series of embarrassing revelations and controversies, including the withdrawal of the blockbuster painkiller Vioxx last year because of safety concerns, a protracted battle over the Plan B morning-after contraceptive pill, and the sudden resignation of FDA Commissioner Lester Crawford, which remains shrouded in mystery.
The latest controversy underscores the heightened concern over drug safety, with the scrutiny this time on an earlier stage in the FDA approval process.
"We saw what happened with Vioxx. I don't think we can afford to allow a drug without particularly important benefits to be approved when there is an apparent doubling of major cardiovascular events," Nissen said.
New class of drugs
Pargluva, also known as muraglitazar, is the first of a new class of diabetes drugs known as "dual-action PPARs." Several similar drugs are already on the market to lower levels of blood fats known as triglycerides, raise levels of "good cholesterol" and increase the effectiveness of insulin for diabetics. Drugs like Pargluva were designed to combine those effects into a single pill.
As part of its standard drug-review process, the FDA convened a panel of experts to examine Pargluva on Sept. 9. The committee voted 8-1 to recommend approval. The FDA usually follows the advice of its advisory panels.
Meanwhile, Nissen and two colleagues, alarmed that the only heart specialist on the FDA panel had recused himself because of a conflict of interest, independently reviewed the data from five studies involving 2,374 patients that Bristol-Myers Squib had submitted.
The analysis found those taking the drug had more than twice the risk of death, heart attacks and strokes, and nearly triple the risk when all types of heart problems were included, such as congestive heart failure and a condition known as a transient ischemic attack.
While the number of patients available for the analysis was relatively small, the trends are so clear and consistent that it would be surprising if the higher risk was due to chance, Nissen said, especially given that patients in the studies tended to be healthier than the typical diabetic.
Neither the FDA, the chairman of the advisory panel nor Bristol-Myers Squibb had immediate comment on the report. An FDA spokeswoman said the agency could not discuss the study because it involves a pending drug application.
Closer scrutiny
The single-action PPAR drugs on the market, Avandia and Actos, have been sold long enough to alleviate concerns they may pose similar risks, Nissen said, but he noted that another similar agent, Rezulin, was withdrawn in 2000 because it caused liver problems.
Other dual-action PPAR inhibitors in the pipeline should also be subject to closer scrutiny, he said. "I would say each should be checked individually," said Nissen, who until recently was chairman of the FDA's Cardiovascular and Renal Drugs Advisory Committee.
Kellie Caldwell, a spokesperson for AstraZeneca International, which is developing a similar drug called Galida, said the company was carefully studying its agent to make sure it is safe and effective. "Patient safety is our top priority," she said.