Dual peroxisome proliferator-activated receptor agonist demonstrates significant lipid benefits

Phase 3 clinical trial results have demonstrated that the dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist muraglitazar achieves significant beneficial lipid effects compared with pioglitazone, and the agent also provides long-term glycemic control in type 2 diabetics. The results were reported during the American Diabetes Association (ADA) 65th Annual Meeting in San Diego, Calif.

"Patients with diabetes must be attended to across the global risk spectrum of dyslipidemia, hypertension, insulin resistance, and central obesity," said David Kendall, MD, associate professor of medicine, University of Minnesota Medical School. "These new compounds address 3 of the most critical areas in diabetes: glucose control, triglycerides, and HDL," he said.

The phase 3 trial included 1,159 patients with type 2 diabetes who had not reached adequate glycemic control goals despite daily treatment with 1,500 mg or more of metformin. They were randomized to receive either 5 mg muraglitazar or 30 mg pioglitazone daily for 24 weeks while metformin doses were maintained at baseline levels. Statin therapy was permitted as needed after the first 12 weeks of treatment.

Fasting plasma glucose was reduced 44 mg/dL from baseline in the muraglitazar group and 33 mg/dL in the pioglitazone group (P<.0001). Muraglitazar also produced significantly greater reductions in fasting plasma insulin than pioglitazone (5.0 versus 3.6 microunits/mL; P<.0001).

LIPID BENEFITS

Twelve-week lipid values demonstrated that muraglitazar-treated patients had significant improvements prior to statin initiation. Muraglitazar-treated patients had a 28% reduction in triglyceride levels from baseline compared with a 14% reduction for pioglitazone patients (P=.0001). Among those who had triglyceride levels >150 mg/dL at baseline, muraglitazar produced a 35% reduction versus a 19% reduction for pioglitazone (P<.0001).

HDL levels increased 19% in the muraglitazar group at 12 weeks and 14% in the pioglitazone group (P=.0001). Non-HDL cholesterol decreased 6%, apoB decreased 12%, and free fatty acids decreased 30%, compared with decreases of 1%, 6%, and 21%, respectively, for pioglitazone. The differences were all statistically significant, Dr Kendall said.

In an extension of a previous dose-ranging, phase 2 trial, patients taking 5 mg muraglitazar maintained HbA_1C levels that were 1.52% below baseline after 104 weeks of treatment. "This 2-year durability study shows that the 5-mg dose has remarkable stability of glucose control," Dr Kendall said.

Four muraglitazar patients developed adverse events related to heart failure, compared to 1 patient in the pioglitazone group; all cases resolved with diuretic therapy and/or withdrawal of the study drug. Hypoglycemia occurred in 3 muraglitazar patients and 1 pioglitazone patient, but there were no hypoglycemia-related serious events or study withdrawals, Dr Kendall said.