Muraglitazar lowers blood glucose and helps dyslipidemia seen in diabetes

A novel compound provides long-term lowering of blood glucose levels and improves plasma lipids (fats) that are often a problem in people with type 2 diabetes -- all in a once-daily pill, according to a report presented today at the American Diabetes Association's 65th Annual Scientific Sessions.

"Muraglitazar provided effective and durable blood glucose lowering over two years, and also significantly lowers triglycerides, non-HDL-C, and apolipoprotein B, as well as raising HDL-C, all of which may reduce the risk of cardiovascular disease in people with type 2 diabetes," said David Kendall, MD, Chief of Clinical Services and Medical Director of the International Diabetes Center and Associate Professor of Medicine at the University of Minnesota Medical School, in a recent interview.

"Further, muraglitazar achieved these goals with only one pill a day, which makes it easier for people with type 2 diabetes to manage multiple health problems and may enhance patient compliance," he explained.

Muraglitazar targets the peroxisome proliferator-activated receptors (PPARs). Activator drugs such as muraglitazar are "keys" that fit into receptor "locks," changing cell function. Activator drugs that target PPAR- gamma (the glitazones), which is associated with improvements in insulin sensitivity and glycemic control, have long been successfully used to treat type 2 diabetes. Muraglitazar targets PPAR-gamma as well as PPAR-alpha, which is associated with regulation of lipids (blood fats). As a dual PPAR activator, muraglitazar becomes the first of a novel "glitazar" class.

More than 18 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputations. It is the fifth leading cause of death by disease in the U.S. Type 2 diabetes involves insulin resistance -- the body's inability to properly use its own insulin. It usually occurs in those who are over 45 and overweight, but it has increasingly been seen in obese children and teens in recent years.

Dr. Kendall reported on several studies with muraglitazar.

Initially, a double-blind dosing trial was done. It involved 985 patients given, by random selection, one of five different once-daily doses of muraglitazar (0.5 - 20 mg.) or pioglitazone 15 mg. All participants were in their mid-50s, generally obese, and had diabetes for five to six years. The group was roughly balanced between men and women. At the initiation of the study, all had inadequate blood glucose control on diet and exercise. Based on this study, the 5 mg. dose was selected for further study. This short- term, 24-week dosing trial also was the base from which the subjects for the next trial were extracted.

A pre-planned open study of the durability of muraglitazar drew on 157 people who had been in the dosing trial and had previously been in the 5 mg. arm. Of these 157, subsequently 36 withdrew from the study, and 33 were unable to achieve adequate control of glucose at 5 mg. The remaining 88 participants who continued on 5 mg. for the entire two-year trial achieved very tight control of blood glucose levels.

"The patients on muraglitazar went from poor control -- an average A1C of 8.0 percent -- to an excellent level of control -- an average of 6.5 percent by the 20th week -- and then maintained that level of control over two years," reported Dr. Kendall. The American Diabetes Association's recommended A1C target in type 2 diabetes is under 7.0 percent.

"It is well known that type 2 diabetes is a progressive disease and deterioration in control is commonly observed in people who are treated with conventional glucose-lowering therapies, such as the sulfonylureas and metformin," noted Dr. Kendall. "However, medications that target insulin resistance, such as the PPAR-gamma activators, may improve the ability of the beta cells in the pancreas to secrete insulin which helps patients to achieve their glucose control goals and sustain them over time."

A type of dyslipidemia commonly seen in people with type 2 diabetes is a cluster of abnormalities including: elevated triglycerides, reduced levels of HDL cholesterol, and a shift toward smaller and denser LDL-cholesterol particles, although total and LDL cholesterol levels may be normal or elevated. A number of these problems seemed to be improved by muraglitazar.

In the next study reported by Dr. Kendall, the drug was evaluated in 1,159 patients with type 2 diabetes, all of whom were taking the anti-diabetes drug metformin. All continued to take metformin but were also randomized in double-blind, randomized fashion to receive either 5 mg. muraglitazar or 30 mg. pioglitazone (which activates only PPAR gamma) once daily. After 24 weeks, the muraglitazar group lowered blood glucose by 1.14 percent vs. 0.85 percent for the pioglitazone group.

Further, the differences in lipids were also greater for muraglitazar vs. pioglitazone, respectively:

• triglycerides: -28.4 percent vs. -13.4 percent;
• HDL-C (the "good" cholesterol): +19.2 percent vs. +13.6 percent;
• non-HDL-C (LDL, the "bad" cholesterol, plus the cholesterol contained in triglyceride-rich lipid particles): -5.9 percent vs. -1.2 percent;
• apolipoprotein B (a protein found in important lipid particles): 11.8 percent vs. -6.0 percent.

"Muraglitazar treatment resulted in greater improvement in both glucose control and lipids when added to metformin when compared to pioglitazone plus metformin," emphasized Dr. Kendall. Both glucose control and dyslipidemia are believed to play an important role in the greater risk of heart attacks and strokes seen in people with diabetes.

The most common side effects seen in the trials were edema that occurred in 5 percent to 8 percent of the durability study participants, as well as weight gain of 2 lbs. to 10 lbs. Dr. Kendall explained that weight gain is typical with commonly used diabetes treatments because as blood glucose levels improve, the calories circulating as glucose are available to be stored in cells for later use, unless they are promptly burned for energy.