Muraglitazar, a dual (α/γ) PPAR activator:: A randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes

Background: Peroxisome proliferator-activated receptors (PPARs) present a therapeutic target, and simultaneous activation of PPAR-alpha and PPAR-gamma may provide improvements in glycemic control and dyslipidemia in patients with type 2 diabetes. Objective: The goal of this study was to evaluate the efficacy and safety of muraglitazar, a dual (alpha/gamma) PPAR activator, in adult patients with type 2 diabetes whose disease was inadequately controlled by diet and exercise. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 24-week monotherapy study in drug-naive, type 2 diabetes patients with inadequate glycemic control. Men and women aged 18 to 70 years with a body mass index <= 41 kg/m(2) and serum triglyceride levels <= 600 mg/dL were eligible for study participation. The study included double-blind and open-label treatment phases. Patients with glycosylated hemoglobin (HbA(1c)) levels >= 7.0% and <= 10.0% at screening were enrolled in the double-blind treatment phase. These patients received treatment with muraglitazar 2.5 mg, muraglitazar 5 mg, or placebo. Patients with HbA(lc) levels > 10.0% and <= 12.0% who met all other study criteria were eligible for enrollment in a 24-week, open-label evaluation of muraglitazar 5 mg. The primary end point was the mean change from baseline in HbA(lc). levels after 24 weeks of treatment. Results: A total of 340 patients (179 men, 161 women) participated in the double-blind treatment phase of the study. Patients had mean baseline HbA(lc) levels of 7.9% to 8.0%. Monotherapy with muraglitazar 2.5 and 5 mg significantly reduced HbA(lc): levels (-1.05% and -1.23%, respectively) compared with placebo (-0.32%; P < 0.001). At week 24, 58%, 72%, and 30% of the patients receiving muraglitazar 2.5 mg, muraglitazar 5 mg, and placebo, respectively, achieved the American Diabetes Association-recommended HbA(Ic) goal of < 7.0%. Fasting plasma glucose, free fatty acids, and fasting plasma insulin levels significantly decreased during muraglitazar treatment (P < 0.001), suggesting an increase in insulin sensitivity. Muraglitazar 2.5 and 5 mg provided improvements from baseline in triglyceride (-18 % and -27%), high-density lipoprotein (HDL) cholesterol (10% and 16%), apolipoprotein B (-7% and -12%), and non-HDL cholesterol levels (-3% and -5%) (P < 0.05 vs placebo for each). In a parallel, open-label cohort of 109 drug-naive patients (56 men, 53 women; mean baseline HbA(lc) level, 10.6%), muraglitazar 5 mg decreased the overall mean HbA(lc) level from baseline by 2.62% (last observation carried forward) and by 3.49% in the 62 patients completing 24 weeks of study. Changes in lipid parameters during open-label treatment were similar to those observed during double-blind treatment. Muraglitazar was generally well tolerated. Edema-related adverse events of mild to moderate severity occurred in 8% to 11% of patients in all groups. Mean changes from baseline weight in the double-blind treatment groups were 1.1 kg for muraglitazar 2.5 mg, 2.1 kg for muraglitazar 5 mg, and -0.8 kg for placebo (P < 0.001); there was a mean 2.9-kg increase in the open-label muraglitazar 5-mg group. Conclusion: In this study, 24 weeks of treatment with muraglitazar 2.5 or 5 Ing was an effective treatment option for these patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.