Muraglitazar May Help Lower Glucose and Cholesterol Levels in Type 2 Diabetes

June 13, 2005

Bonnie Darves

June 13, 2005 (San Diego) — Results of a new study signal major progress in the development of a new activator compound that addresses a prevalent "twin" problem in type 2 diabetes — elevated plasma lipid levels in conjunction with the typical elevated glucose levels — in a two-in-one pill, according to researchers here at the American Diabetes Association's 65th Annual Scientific Sessions.

Reporting on two-year results of the phase 3 trial of the peroxisome proliferator-activated receptor alpha/gamma (PPAR alpha/gamma) muraglitazar, researchers said that the apparent efficacy of the compound itself — better glucose control and a nearly 30% decrease in triglyceride levels — and the dual-target approach PPARs may signal a new era in treating diabetes.

"This [PPAR alpha/gamma] is the next step in the management of multiple risk factors for diabetes because the thing these compounds possess, in a sense, is all of the benefits of insulin sensitizers with, we hope, the established benefits of the fibrates," said the study's chief author David Kendall, associate professor of medicine at the University of Minnesota Medical School in Minneapolis, and medical director of the International Diabetes Center. "The challenge, however, is that clinicians have not really picked up on using combination drugs that we already have like those that target both blood pressure and cholesterol. It remains to be seen whether physicians will begin thinking about insulin resistance, glucose, and lipids more broadly, as a single disorder, even though we know that lipid disorders and insulin resistance are bedfellows. That is a brand new way of thinking."

Muraglitazar (Bristol-Meyers Squibb) is one of a handful of novel dual alpha/gamma PPARs called glitazars that activate PPAR-gamma to lower glucose levels while simultaneously targeting the PPAR-alpha to reduce triglyceride concentrations and enable high-density lipoprotein (HDL) cholesterol increases.

The two-year results reported here involved an extension study of 157 participants who continued taking muraglitazar for two years following an initial 985-patient randomized dosing trial that compared five different doses of muraglitazar (0.5 - 20 mg) with 15 mg of pioglitazone. The 88 patients who completed the extension study (who were in their mid-50s and had had type 2 diabetes for at least five years) and continued taking 5.0 mg daily of muraglitazar achieved an average hemoglobin A1C level of 6.5% four months after initiation of muraglitazar. Patients retained that tight control throughout the two-year period, Dr. Kendall said. Triglyceride levels decreased 28.4% in patients taking muraglitazar and HDL cholesterol levels increased 19.2%. Thirty-three patients withdrew from the durability study because they were unable to achieve adequate glucose control while taking 5 mg of muraglitazar. The most common adverse effects seen in the study were edema, which affected 8% of participants, and weight gain ranging from 2 to 10 lb among participants in the durability study. Those adverse effects have been seen in all studies of PPAR alpha/gamma and occur with use of glitazones, but in most cases have been moderate and have not led to congestive heart failure in patients who do not have underlying heart disease.

Commenting on developments in glitazars and on newly published results on both muraglitazar and tesaglitazar, endocrinologist Barry Goldstein, MD, PhD, director of the Division of Endocrinology, Diabetes and Metabolic Diseases at Jefferson Medical College in Philadelphia, Pennsylvania, said that the next challenge will be balancing adverse effects without compromising benefits. "I think the PPAR-alpha is a good target and companies are trying to develop more potent drugs that work through PPAR-alpha and at the same time … improve on the PPAR-gamma. Companies are trying to get the glucose lowering and perhaps lose some of the adverse effects, but that has been a problem," Dr. Goldstein said, adding that glitazars may have a place but likely will not soon "replace the medications we use now."

Dr. Kendall concurred, explaining that even if the glitazars move forward and receive U.S. Food and Drug Adminstration approval, they will not become a single solution. "This will not replace medications like Actos [pioglitazone; Takeda]. Rather, it will be a new tool in our toolbox to meet the unmet needs of our patients with diabetes who have a coexisting lipid disorder," Dr. Kendall said.

ADA 65th Annual Scientific Sessions: Abstracts 967, 14-OR. Presented June 12, 2005.

Reviewed by Gary D. Vogin, MD

Bonnie Darves is a freelance writer for Medscape.

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