New Medication Awaiting FDA Approval For Patients With Type 2 Diabetes Causes Complications
A new medication under review by the Food and Drug Administration that may regulate blood glucose levels and have a beneficial effect on blood cholesterol and lipid levels for patients with Type 2 diabetes appears to increase the risk for major adverse cardiovascular events and death, according to a new study in JAMA. The study and an accompanying editorial were released early online today at www.JAMA.com because of their timeliness and potential importance for public health.
The medication, muraglitazar, is in a class of drugs called dual peroxisome proliferator-activated receptors (PPARs), that affect lipid levels and glycemic control 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 a 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.
Steven E. Nissen, M.D., and his colleagues from the Cleveland Clinic Foundation, reviewed the FDA briefing documents available via the FDA website for the September 9 public hearing. The scientists 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 scientists restricted their analysis to treatment groups using muraglitazar doses of 5 mg/d 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 PPAR) and 529 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 the diabetes control among the participants was relatively poor.
"In the muraglitazar-treated patients, death, MI (heart attack), 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 write. "For the most widely accepted composite end point of death, MI (heart attack), and stroke the RR (relative risk) for muraglitazar was 2.23. Other end points using narrower definitions (including only cardiovascular death) or broader composites (including CHF [congestive heart failure] and TIA [transient ischemic attack] events) showed similar risks." The scientists note 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 scientists state that "atherosclerotic cardiovascular disease is particularly common in patients with type 2 diabetes, representing the cause of death in approximately 80 percent of diabetic patients. Thus, any drug used to treat diabetes requires careful scrutiny for its effects on atherosclerosis-related outcomes, such as MI and stroke." The scientists also note there are some limitations to their analysis as 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 RRs indicating a doubling for irrevocable, major end points and composite outcomes. The consistency of these RRs 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," the authors conclude.
(JAMA. 2005;294:doi:10.1001/jama.294.20.joc50147). Available pre-embargo to the media at www.jamamedia.org).