Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

Abstract

OBJECTIVE -We sought to evaluate the effects of muraglitazar, a dual (␣/␥) peroxisome proliferator-activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities. RESULTS -Analyses were conducted at week 24 for HbA 1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (Ϫ1.14% from baseline), and pioglitazone reduced mean A1C to 7.28% (Ϫ0.85% from baseline; P Ͻ 0.0001, muraglitazar vs. pioglitazone). At week 12, muraglitazar and pioglitazone reduced mean plasma triglyceride (Ϫ28 vs. Ϫ14%), apolipoprotein B (Ϫ12 vs. Ϫ6%), and non-HDL cholesterol (Ϫ6 vs. Ϫ1%) and increased HDL cholesterol (19 vs. 14%), respectively (P Ͻ 0.0001 vs. pioglitazone for all comparisons). At week 24, weight gain (1.4 and 0.6 kg, respectively) and edema (9.2 and 7.2%, respectively) were observed in the muraglitazar and pioglitazone groups; at week 50, weight gain and edema were 2.5 and 1.5 kg, respectively, and 11.8 and 8.9%, respectively. At week 50, heart failure was reported in seven patients (five with muraglitazar and two with pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from perforated duodenal ulcer in the pioglitazone group. RESEARCH DESIGN AND METHODSCONCLUSIONS -We found that 5 mg muraglitazar resulted in greater improvements in A1C and lipid parameters than a submaximal dose of 30 mg pioglitazone when added to metformin. Weight gain and edema were more common when muraglitazar was compared with a submaximal dose of pioglitazone.

Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

“…Several combined (dual) PPARa/g agonists have reached phase III trials -muraglitazar (Kendall et al 2006), tesaglitazar (Bays et al 2007), and aleglitazar (Henry et al 2009) -and although the development of muraglitazar and tesaglitazar was terminated because of safety concerns, the therapeutic potential of PPARa/g agonists remains of high clinical interest. To our knowledge, the effect of combined activation of PPARg and PPARa on bone biology has not been investigated previously.…”

Peroxisome proliferator-activated receptors: Targets for the treatment of metabolic illnesses (Review)

“…On the other hand, a recently published study on muraglitazar and pioglitazone, either alone or in combination with metformin, showed a significant improvement in HbA IC and in lipid profiles (66).…”

“…In another study of non-diabetic patients with coronary cardiopathy, it was shown that rosiglitazone reduced not only inflammation markers but also the endothelial activation markers E-selectin, Von Willebrand factor, fibrinogen and CRP (66).…”

Current and novel therapies for the treatment of nonalcoholic steatohepatitis

“…A number of such agents have recently been developed, including muraglitazar, tesaglitazar, naveglitazar, and netoglitazone [61]. In early trials, these agents reduced levels of circulating triglycerides, increased HDL levels, and improved insulin sensitivity [62][63][64]. An amelioration in the PPARc-mediated weight gain via a PPARa-associated decrease in food intake and lipid oxidation has been demonstrated in animals [62,65], but these results are yet to be replicated in humans.…”