Investigational Diabetes Drug Linked to Increased Risk of Death, Strokes and Heart Attacks
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Researchers here said today that the use of the investigational diabetes drug Pargluva (muraglitazar) doubles the risk of death, heart attack and stroke, and they asked the FDA to delay approval of the drug.
In an analysis that was released online by the Journal of the American Medical Association, Steven E. Nissen, M.D., and colleagues at the Cleveland Clinic said the FDA should not approve Pargluva until its cardiovascular safety can be proven in “a dedicated cardiovascular events trial.”
The drug is a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) activator, which means that it targets both hemoglobin A1C and serum lipids.
Last month an FDA advisory committee recommended approval of Pargluva by a vote of eight to one, and two days ago the FDA issued an “approvable letter” to Bristol-Myers Squibb and Merck & Co., which are jointly developing the drug. The FDA letter asked for more data about cardiovascular safety.
In results reported at the American Diabetes Association meeting last June, two years of daily treatment with Pargluva was associated with an average reduction of 1.5% in baseline HbA1C and a by 22% decrease in triglycerides as well as a 29% increase in HDL.
But patients taking the drug also gained about 13 pounds on average.
In response to the JAMA article, a Bristol-Myers Squibb spokesman said, “Following the receipt of an approvable letter for Pargluva (muraglitazar) earlier this week, Bristol-Myers Squibb and Merck said that we are 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. Pargluva was extensively studied and all available data were reported to the FDA. This information was presented by Bristol-Myers Squibb and the FDA at a recent advisory committee meeting, an open, public forum.”
Dr. Nissen, who is also president-elect of the American College of Cardiology, said in an interview that he “dropped everything” when he saw the FDA briefing documents, which were prepared by FDA staffers last month for the advisory committee, and began a detailed analysis of the trial data. “Frankly, when I read the briefing documents, the excess of cardiovascular events struck me as a smoking gun,” he said.
The Cleveland Clinic analysis was based on phase II and phase III trial results filed with the FDA. Those prospective, randomized double-blind controlled trials enrolled 3,725 patients with type 2 diabetes. Patients were randomized to various doses of Pargluva, Actos (pioglitazone), or placebo as monotherapy or in combination with Glucophage (metformin) or Glucovance (glyburide).
There was death, MI, or stroke in 35 of 2,374 (1.47%) patients treated with Pargluva and in nine of 1,351 (0.67%) patients in the placebo or Actos control arms. The relative risk of death, MI or stroke was 2.23 in the Pargluva patients (95% CI 1.07-4.66; P=0.03). The relative risk of congestive heart failure was 7.4 in the Pargluva group (95% CI 0.97-56.8; P=0.053).
When transient ischemic attacks (TIA) and congestive heart failure are included in the analysis, the relative risk increases to 2.62 (95% CI 1.36-5.05; P=0.004), Dr. Nissen said.
Moreover when the components of the endpoint are analyzed individually, the relative risk was higher in each component category for Pargluva-treated patients, but this increase was not statistically significant.
Dr. Nissen said, however, that the analysis is limited because he and his colleagues only had access to data included in the FDA filing rather than data from the original clinical trial databases.
In an editorial that accompanied the JAMA study, James M. Brophy, M.D., Ph.D., wrote that the analysis by Dr. Nissen and colleagues was meticulous and it “should focus serious attention on the cardiovascular risks of this drug.” He added that also unanswered are “residual safety concerns surrounding carcinogenicity also have not been completely resolved.”
This is not the first time that Dr. Nissen has waved a red flag at a non-cardiac drug. In 2001 he was lead author of a JAMA study that reported increased cardiovascular risks associated with Vioxx (rofecoxib). At the time, Merck, which made Vioxx, adamantly denied his claims, but on September 30, 2004, the company pulled the drug from the market when studies found an increased risk of cardiovascular events in patients who took the drug for 18 months or longer.
“Just as in 2001 we are talking about a very small number of events, but the difference between now and 2001 is that now we have time to act before the drug is approved,” said Dr. Nissen. “There is no need to rush this drug to market since we have excellent drugs that treat blood sugar and other excellent drugs for treating lipids.”
“We should demand a very high standard for demonstrated safety for a drug that has no additional benefit, but doubles the risk of very serious events,” he said.
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