A new diabetes pill that was headed for government approval has been linked to deaths, heart attacks and strokes, a medical journal reported in an analysis it said was rushed online to head off a Vioxx-like fiasco.

The study by leading heart researchers found twice as many deaths and cardiovascular problems in diabetic adults taking the drug Pargluva as those on dummy pills or a competing drug.

Developed by Bristol-Myers Squibb and Merck & Co., the drug, known generically as muraglitazar, was endorsed by a Food and Drug Administration panel last month. It is a treatment for Type 2 diabetes, the most common form of the condition and one that occurs most often in people who are overweight.

The Journal of the American Medical Association said it posted the analysis on its Web site Thursday ahead of next month's publication date because of public safety concerns. The study was by Cleveland Clinic doctors who reviewed data the FDA made public before the panel vote.

If the analysis is correct, the drug could have meant a "public health catastrophe" given that 18 million Americans have diabetes, said Dr. Steven Nissen, who worked on the analysis with Dr. Eric Topol and a clinic statistician.

"This is the Vioxx that isn't going to happen," Nissen said, referring to the popular painkiller Merck removed from the market last year after it was linked with serious heart problems. Nissen has done consulting work for several drug companies, including Merck and makers of other diabetes treatments, but said he does not accept fees for that work.

Critics including Nissen have accused the FDA of lax drug surveillance because of Vioxx and other recent safety issues, such as evidence linking some antidepressants with a greater risk of suicidal thoughts in youngsters.

The FDA appeared to be heading down the same road with Pargluva despite that criticism, said Dr. Catherine DeAngelis, JAMA's editor in chief.

"It is beyond me why individuals who are supposed to be overseeing the safety of the public would take a chance when it's not necessary," DeAngelis said.

In a statement, the FDA said it appreciates "the need for careful assessment of risk versus benefit for all drugs, particularly those indicated for long-term, preventive therapy."

"The FDA has made significant investments of resources and expertise in developing fundamentally better methods for identifying and monitoring cardiovascular safety issues with all drugs."

Bristol-Myers Squibb and Merck issued a written statement Thursday that said Pargluva "was extensively studied and all available data were reported to the FDA."

Pargluva would be the first diabetes drug on the market designed to lower blood sugar, reduce fatty triglycerides and increase levels of "good" cholesterol, Nissen said. Other drugs achieve those results individually, said Dr. Peter Lurie, deputy director of the Public Citizen Health Research Group, a consumer advocacy group.

The analyzed data involved 3,725 patients who took Pargluva or a drug called pioglitazone or dummy pills in different studies lasting from 24 weeks to 104 weeks.

Deaths, heart attacks or strokes occurred in 35 of the 2,374 Pargluva patients versus nine of 1,351 patients in a combined group on the other drug or on dummy pills. Increased risks for mini-strokes and heart failure also were found among Pargluva patients.

A JAMA editorial notes that the new analysis contrasts sharply with data company sponsors presented to the FDA showing no significant excess risk of death or cardiovascular problems.

Company-provided data might have fostered an "illusion of safety" because of numerous omissions, such as excluding patients most likely to face cardiovascular risks, including elderly diabetics, said editorial author Dr. James Brophy of McGill University.

The drug had been projected to bring the companies $1 billion yearly, and DeAngelis contended that money appeared to trump safety.

Pargluva's makers said earlier this week they had received a letter from the FDA that indicated the drug was "approvable" but which also asked for more safety data on the drug's cardiovascular effects.

Nissen said final FDA action had been expected next week. The agency often follows recommendations from its advisory panels.

It's uncertain how quickly the companies can produce the data FDA wants, but the new analysis now puts approval in doubt, said Lurie, the official with Public Citizen, which had presented similar safety concerns to the FDA panel.

"An article by two such prominent cardiologists could be the nail in the coffin for this drug," he said. "It's going to make it much more difficult for (the FDA) to look at whatever data the companies submit and conclude that the drug should be approved."

Even without the JAMA article, the drug likely would not have hit the market for at least several months, Lurie said.

In their written statement Thursday, Bristol-Myers Squibb and Merck said that after receiving the FDA's letter requesting more data, they were "eager to begin discussions with the FDA to address more fully the cardiovascular safety profile of the compound and to determine what additional information may be necessary."

Reference Source 102
October 21, 2005