WASHINGTON — Muraglitazar, a novel agent targeting both glucose and lipid levels, is an effective monotherapy option for patients with type 2 diabetes, Robert Frederich, M.D., and his associates reported at the annual meeting of the American Association of Clinical Endocrinologists.
In the first phase III data to be released by comarketers Bristol-Myers Squibb Co. and Merck & Co., muraglitazar effectively lowered hemoglobin A1c and triglycerides and raised HDL cholesterol levels in a 24-week, randomized, double-blind, placebo-controlled trial of drug-naive adults with type 2 diabetes who were inadequately controlled with diet and exercise alone, said Dr. Frederich, of Bristol-Myers Squibb in Princeton, N.J., and his associates.
The New Drug Application for muraglitazar is under review by the Food and Drug Administration. If approved, the drug would be the first of the new class called “glitazars,” agents that activate both α and γ peroxisome proliferator-activated receptors (PPARs).
The PPARs, members of the steroid hormone nuclear receptor family, are already established as therapeutic targets for treating diabetes and dyslipidemia: The thiazolidinedione class of glucose-lowering agents are PPAR-γ agonists, while fibrates improve lipid profiles via PPAR-α activation, Jorge Plutzky, M.D., explained at a satellite symposium sponsored by Bristol-Myers Squibb and Merck held during the AACE meeting.
“Such drugs hold out the potential for combining PPAR-α's lipid improvements, the PPAR-γ's insulin-sensitizing effects, and the possible anti-inflammatory/antiatherosclerotic effects of both receptors,” said Dr. Plutzky, director of The Vascular Disease Prevention Program at Brigham and Women's Hospital, Boston.
According to AACE past president Paul Jellinger, M.D., “combo pills are becoming more common and more accepted by many [physicians] largely because of reduced copayment.
Dual PPARs may be useful because the triglyceride/HDL part of diabetic dyslipidemia often gets overlooked in favor of straight LDL lowering with statins,” he told this newspaper after the meeting.
Most diabetics are already on lipid-lowering therapy, and statin therapy sometimes adequately addresses diabetic dyslipidemia, but often it does not. “On balance, I believe dual PPAR's will be a sensible and useful addition,” said Dr. Jellinger, of Hollywood, Fla.
The study patients were adults aged 18–70 years who had a mean baseline hemoglobin A1c between 7% and 10%. None were on antihypertensive therapy in the 4–6 weeks before the study. Therapy with a stable dose of statins was allowed through the first 12 weeks of the trial.
A total of 111 patients were randomized to receive 2.5 mg of muraglitazar daily, 114 took 5.0 mg, and 109 received placebo. In a separate open-label trial, another 109 patients with baseline A1c values of 10%–12% received 5.0 mg of muraglitazar daily, Dr. Frederich and his associates reported in a poster presentation.
At 24 weeks, the mean A1c values dropped from 8.02% to 6.96% (−1.05) in the 2.5-mg muraglitazar group, from 7.89% to 6.68% (−1.23) in the blinded 5.0-mg patients, and from 10.68% to 8.06% (−2.62) in the open-label 5.0-mg group. In contrast, A1c levels among the placebo patients fell by an insignificant 0.32 percentage points, from 7.99% to 7.67%.
In the randomized trial, 67% of the 2.5-mg group and 74% of the 5.0-mg group achieved the American Diabetes Association's A1c target of less than 7.0%, compared with 32% of the placebo patients. The proportions who dropped below the AACE's 6.5% cutoff were 58%, 36%, and 18%, respectively. Fasting plasma glucose and insulin levels also were significantly reduced in both muraglitazar dosage groups in the double-blind trial, they said.
Triglyceride levels in the double-blind trial decreased significantly by 18% with 2.5 mg of muraglitazar and by 27% with 5.0 mg, compared with just 2% for placebo. In the open-label trial, triglycerides were reduced by 31%. Among the patients with baseline triglycerides of 150 mg/dL or above, reductions at 24 weeks were 24.8% with 2.5 mg of muraglitazar, 30.4% with 5.0 mg, 13.2% with placebo, and 31% in the open-label trial with 5.0 mg.
Mean HDL cholesterol levels rose by 10% and 16% with 2.5 mg and 5.0 mg of muraglitazar, respectively, in the blinded trial, both significant increases compared with the 2% rise with placebo. Levels of LDL cholesterol didn't change significantly with muraglitazar, but levels of apolipoprotein B, free fatty acid, and non-HDL cholesterol did, Dr. Frederich and his associates reported.
Adverse events occurred in 71% of patients with 2.5 mg of muraglitazar, 77% with 5.0 mg, 69% with placebo, and 70% in the open-label 5.0-mg group, with serious adverse events in 3%–4% of all groups with no significant differences between them. There were no cases of heart failure.
Edema-related events occurred in 8% with 2.5 mg, 11% with 5.0 mg, 8% with placebo, and 9% in the open-label group. All events in the muraglitazar patients were mild to moderate, while one placebo patient experienced serious edema. No patient treated with muraglitazar discontinued the study due to edema, but two placebo patients did.