Nissen SE et al. (2005) Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294: 2581–2586

An FDA advisory committee recently recommended approval of muraglitazar, an agonist for both peroxisome proliferative-activated receptors α and γ, as monotherapy for type 2 diabetes and as combination therapy in patients with blood glucose inadequately controlled by metformin. Nissen et al. reanalyzed the data presented to the advisory committee, obtained from publicly disclosed FDA documents. The authors sought to determine the risk of cardiovascular events in patients treated with muraglitazar, compared with controls.

Overall, 2,374 muraglitazar-treated patients and 1,351 controls (823 taking the comparator drug pioglitazone and 528 placebo) with type 2 diabetes were included, from one phase II and four phase III trials. Patients treated with muraglitazar doses ≥10 mg were excluded, as approval for these doses was not sought. Cardiovascular death, congestive heart failure, transient ischemic attack, nonfatal myocardial infarction or nonfatal stroke occurred in 2.11% of patients taking muraglitazar versus 0.81% of controls (relative risk = 2.62; P = 0.004).

The analysis by Nissen et al. was limited to data available through the FDA website and could not, therefore, allow a more complex statistical analysis; however, considering the number of adverse events in the short period (24–104 weeks) of these trials, the authors recommended that FDA approval for muraglitazar be postponed. The FDA subsequently stated that muraglitazar would not be approved without further long-term cardiovascular safety data (SE Nissen, personal communication).