The FDA recently issued an approvable letter for
muraglitazar (Pargluva), a peroxisome proliferator–activated
receptor (PPAR) agonist with both PPAR-
and PPAR-
effects, for the
management of type 2 diabetes. PPAR-
agonists lower
triglyceride levels and increase HDL levels, and PPAR-
agonists increase
insulin sensitivity. (An approvable letter from the FDA indicates
that the agency is leaning toward approval but that the decision
is not yet final.)
Prompted by concerns about potential harms from dual-PPAR agonists, researchers
reviewed data from five clinical trials of muraglitazar that the FDA
had published on its website. The subjects were 3725 adults with type
2 diabetes (age
70; body-mass index
<41; HbA1c level, 7%–10%) assigned to receive
muraglitazar (
5 mg/day) or a
control treatment (placebo or the PPAR-
agonist pioglitazone),
either as monotherapy (2 trials) or as part of combination therapy
involving metformin or glyburide (3 trials).
The composite incidence of death, MI, or stroke was significantly greater among muraglitazar recipients than among controls (1.47% vs. 0.67%; relative risk, 2.23; P=0.03). Including transient ischemic attack and heart failure in the endpoint widened the difference (2.11% vs. 0.81%; RR, 2.62; P=0.004). No individual endpoint showed a significant difference, although RRs exceeded 2.0 in all cases, with the greatest difference in adjudicated heart failure (0.55% vs. 0.07%; RR, 7.43; P=0.053).
These data raise important concerns about using muraglitazar in clinical practice. Questioning the FDA’s approval process, an editorialist urges paying serious attention to the potential harms associated with the drug before it is used widely.
References:
1. Nissen SE et al. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005 Oct 20; 294.
2. Brophy JM. Selling safety — Lessons from muraglitazar. JAMA 2005 Oct 20; 294.