PEROXISOME PROLIFERATOR–ACTIVATED RECEPTORS (PPARs) are nuclear cell transcription factors with isoform agonists that exhibit clinical benefit. The PPARagonists increase insulin sensitivity, explaining the antidiabetic action of the thiazolidinediones rosiglitazone and pioglitazone. PPARagonists, including the fibrates, increase fatty acid oxidation, leading to a decrease in plasma triglycerides and a modest increase in highdensity lipoprotein cholesterol. Muraglitazar is the first dualPPAR agonist to be considered for general marketing both as monotherapy and combined therapy by the US Food and Drug Administration (FDA). Given the emerging epidemic of type 2 diabetes, it is easy to understand the enthusiasm for this new class of drugs. Tight glycemic control reduces diabetic microvascular complications, although both old and new studies have failed to convincingly show decreased macrovascular complications of stroke, cardiac disease, and peripheral vascular disease. On September 9, 2005, an FDA advisory committee reviewed muraglitazar’s efficacy and safety data and recommended approval and on October 18, 2005, it was reported that the FDA issued an “approvable letter” for this drug. However, in this issue of JAMA, Nissen and colleagues have reanalyzed these data and challenge the advisory board’s recommendation. Courtesy of a transparent FDA approval process that provides online submission information, Nissen et al were able to contrast the 2374 patients taking muraglitizar at 5 mg or less vs the combined 1351 patients exposed to either placebo or pioglitazone. Their analysis demonstrated a 2.23 (95% confidence interval, [CI], 1.07-4.06) increased risk in the composite outcome of death, myocardial infarction, or stroke and a 7.4 (95% CI, 0.97-56.8) relative risk of congestive heart failure (CHF). The authors rightly mention that a potential limitation of their analysis was their use of simple proportion tests and not the more informative survival time analysis. Nevertheless they feel confident in recommending that approval of muraglitazar be delayed pending a dedicated cardiovascular trial. In contrast, the sponsor’s presentation to the advisory committee concluded that no significant excess risk of deaths or cardiovascular events occurred with muraglitazar treatment. While there may be disagreement over which analysis to believe, a consensus should exist that these differences indicate less than robust data. Is it possible, at least partially, to reconcile these radically different interpretations of the same data? Unlike the report by Nissen et al, the sponsor presented the data as 3, not 2, distinct groups and calculated event rates per patient year of exposure (TABLE), thereby logically weighting by duration of exposure. However the 495 patients, representing 990 patient-years of exposure, with subtherapeutic doses of 2.5 mg or less were maintained in the denominator. Since FDA approval was not sought for these small doses of muraglitazar, the inclusion of these data in the safety analysis for the proposed marketed doses may be questioned. Because there were no associated cardiovascular events among these patients, the effect is a dilution of the clinically pertinent risk estimate. The recalculated event rate for the proposed marketed doses of muraglitazar is 97 events per 2447 patient-years, an excess of 20% compared with placebo alone and an excess of 67% compared with the combined placebopioglitazone control group. There is obvious variability in cardiovascular event rates across the 5 different trials, but this heterogeneity can only be properly explored with further studies. Muraglitazar users also had a 2to 4-kg increase in weight, a 10% incidence of edema, and 13 adjudicated cases of CHF (compared with 1 case in the control group) despite the strict exclusion of all patients with moderate or severe baseline CHF. Although patients with mild CHF symptoms (New York Heart Association class I and II) were eligible, only 25 were recruited and since their CHF risk was increased 10fold, the sponsor’s claim that safety has been demonstrated for this group rings hollow. Systematic baseline ejection fractions were not recorded but none of the patients had a value below 40%, implying that CHF risk prediction for future muraglitazar users will likely be problematic. These elevated CHF rates are possibly related to increased circulating volume and have been consistently observed with other PPARagonists. Moreover, the rates from these clinical