title: Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes.
abstract: 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 < or =41 kg/m(2) and serum triglyceride levels < or =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 > or =7.0% and < or =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(1c) levels >10.0% and < or =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(1c) 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(1c) levels of 7.9% to 8.0%. Monotherapy with muraglitazar 2.5 and 5 mg significantly reduced HbA(1c) 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(1c) 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(1c) level, 10.6%), muraglitazar 5 mg decreased the overall mean HbA(1c) 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.
  
  
  CONCLUSIONS
  In this study, 24 weeks of treatment with muraglitazar 2.5 or 5 mg was an effective treatment option for these patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, 27599, USA. jbuse@med.unc.edu
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.forename: Cindy J
authors.initials: CJ
authors.lastname: Rubin
authors.forename: Robert
authors.initials: R
authors.lastname: Frederich
authors.forename: Kalyanee
authors.initials: K
authors.lastname: Viraswami-Appanna
authors.forename: Kwo-Chuan
authors.initials: KC
authors.lastname: Lin
authors.forename: Rafael
authors.initials: R
authors.lastname: Montoro
authors.forename: Gerald
authors.initials: G
authors.lastname: Shockey
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D005215:Fasting / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000627:therapeutic use*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D005998:Glycine; D007004:Hypoglycemic Agents; D007328:Insulin; D010080:Oxazoles; D047492:Peroxisome Proliferator-Activated Receptors; C500085:muraglitazar