A new review of trial data indicate that muraglitazar, a drug for type 2 diabetes not yet approved for use in the US, appears to increase risk for major adverse cardiovascular events and death, according to an article published online October 20th by the Journal of the American Medical Association.

The new medication, which is in the drug class called dual peroxisome proliferator-activated receptor agonists, is intended to benefit lipid and glucose levels in diabetic patients. The studies on muraglitazar were reviewed by an FDA advisory committee on September 9, 2005, resulting in a vote of 8 to 1 recommending approval for its use as monotherapy in controlling blood glucose levels in patients with type 2 diabetes. On October 18, 2005, the FDA issued an “approvable letter” for muraglitazar, indicating that the drug could be approved once the FDA receives and reviews additional information.

In the current research, Steven E. Nissen, MD, and colleagues from the Cleveland Clinic Foundation, reviewed the FDA briefing documents available for the September 9 public hearing. The researchers analyzed the muraglitazar trials performed in diabetic patients, publicly released by the sponsor and FDA for the advisory panel meeting.

The documents provided data for five clinical trials that assessed safety and efficacy in diabetic patients. The researchers restricted their analysis to treatment groups using muraglitazar doses of 5 mg/day or less. The analysis yielded 2,374 patients exposed to muraglitazar and 1,351 patients exposed to other agents, of which 823 received pioglitazone (a currently available member of the same class) and 529 received placebo.

The patients were relatively young (average age 55 years or less) and obese (average body mass index greater than 30). The studies included both men and women participants, and diabetes control among the participants was relatively poor.

“In the muraglitazar-treated patients, death, myocardial infarction, or stroke occurred in 35 of 2,374 (1.47 percent) patients compared with 9 of 1,351 (0.67 percent) patients in the combined placebo and pioglitazone treatment groups (controls),” the authors found.

“The results of this analysis are concerning,” the authors wrote. “For the most widely accepted composite end point of death, myocardial infarction, and stroke the relative risk for muraglitazar was 2.23. Other end points using narrower definitions (including only cardiovascular death) or broader composites (including congestive heart failure and transient ischemic attack) showed similar risks.”

The researchers noted that the results are particularly concerning because the excess of adverse events was observed after the study participants had limited drug exposure ranging from 24 to 104 weeks.

The researchers noted there are some limitations to their analysis because they did not have access to original trial databases: “Nonetheless, some important conclusions are warranted. Muraglitazar appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment. The estimated magnitude of this risk is substantial with relative ratios indicating a doubling for irrevocable, major end points and composite outcomes. The consistency of these relative ratios suggests that this result is not due to chance. Accordingly, muraglitazar should not be used or approved to treat patients with diabetes until an appropriate dedicated trial to assess cardiovascular outcomes is performed.”