Pioglitazone Helpful in Diabetes Therapy

Laurie Barclay, MD

May 19, 2003

May 19, 2003 -- Two poster presentations at the American Academy of Clinical Endocrinology annual meeting show that pioglitazone, when added to either sulfonylurea or metformin, significantly improves lipid profile as well as glycemic control. A third poster presentation showed that the same combination of drugs does not increase liver transaminase levels and may even reduce ALT levels.

"Two of these trials were similar, looking at the effect of pioglitazone on circulating very-low-density lipoproteins (VLDL) and free fatty acid (FFA) levels, one in combination with sulfonylurea and the other with metformin," Mehmood Khan, MD, vice president of medical and scientific affairs of Takeda Pharmaceuticals North America in Lincolnshire, Illinois, told Medscape. "In both trials, we saw a reduction in VLDL and FFA."

One multicenter, double-blind, 24-week randomized trial compared the effects of 30 mg or 45 mg pioglitazone daily, combined with sulfonylurea, in 702 patients with diabetes mellitus. Compared with baseline levels, VLDL and FFA levels declined significantly at 24 weeks.

There were also improvements in hemoglobin A1c, fasting plasma glucose, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein, and total cholesterol levels. Compared with the 30-mg pioglitazone group, the 45-mg pioglitzaone group had significantly greater increases in HDL ( P <= .05).

In the second trial, a similarly designed study of 827 patients, 30 mg and 45 mg pioglitazone had similar effects when combined with metformin.

"Overall, the data from studies using [pioglitazone] in combination with either metformin or sulfonylureas demonstrated significant decreases in FFA and VLDL, as well as previously published decreases of triglycerides and increased levels of HDL-C," senior author Frederick T. Murray, MD, told Medscape. "These findings were consistent with anticipated improvements, not only to dyslipidemia commonly associated with type 2 diabetes mellitus, but also to cardiovascular risk.

"According to a number of recent epidemiological studies, low HDL, high triglycerides, VLDL, and FFA are all independent risk factors for cardiovascular disease and mortality in patients with type 2 diabetes," Dr. Murray continued. "Ongoing Takeda studies, including PROACTIVE, PERISCOPE, and CHICAGO, are actively collecting both cardiovascular outcomes data and data related to atherosclerosis prevention to further answer questions related to cardiovascular risk and mortality."

The third presentation described two multicenter, double-blind, 24-week randomized trials comparing the effects of 30 or 45 mg pioglitazone daily combined with sulfonylurea (702 patients) or metformin (827 patients).

Only one patient in each trial had an ALT increase greater than three times the upper limit of normal, which suggests no pioglitazone-induced elevations in ALT levels in combination with metformin or sulfonylurea. Furthermore, both studies showed small mean reductions from baseline in ALT levels at all pioglitazone doses.

"In both type 2 diabetes and exogenous obesity there is increased prevalence of elevated liver enzymes, related to nonalcoholic steatorrheic hepatosis," Dr. Khan said. "We thought that treating with an insulin sensitizer such as pioglitazone might decrease intrahepatic fat content. As predicted, liver enzymes decreased."

Takeda Pharmaceuticals North America supported these studies and employs Drs. Murray and Perez, two of the study authors.

AACE 12th Annual Meeting: Abstracts 25, 26, 27. Presented May 14-18, 2003.

Reviewed by Gary D. Vogin, MD



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