SAN DIEGO — Metaglidasen is a novel insulin sensitizer that appears to lower blood glucose as effectively as the thiazolidinediones without causing weight gain or edema, Julio Rosenstock, M.D., reported at the annual scientific sessions of the American Diabetes Association.
The investigational agent, manufactured by Metabolex Inc., is a partial agonist/antagonist of the peroxisome proliferator-activated receptor (PPAR)-gamma. In contrast, the TZDs rosiglitazone and pioglitazone are full PPAR-gamma agonists.
While the TZDs are associated with significant reductions in hemoglobin A1c levels, their use is limited by high rates of weight gain and fluid retention, said Dr. Rosenstock, a practicing endocrinologist in Dallas and clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas.
He presented the results of a phase II multicenter trial conducted in 217 patients with type 2 diabetes who were inadequately controlled on insulin, with a mean baseline hemoglobin A1c of 9.1%. This group was chosen to study first because the risk for fluid retention with TZDs is greatest among patients who use them in combination with insulin, he explained.
After being taken off all oral medications but remaining on the same dose of insulin, the patients were randomized to receive 200 mg or 400 mg of metaglidasen or placebo once daily for 12 weeks. A total of 208 patients completed at least 67 days, the duration deemed necessary to establish drug effect. The numbers who discontinued due to adverse events did not differ between the two metaglidasen groups and placebo.
At 12 weeks, reductions in hemoglobin A1c were statistically significant for both doses of metaglidasen combined with insulin (0.9 percentage point reduction with 200 mg and 1.0 with 400 mg), compared with just 0.3 with placebo plus insulin.
This effect on A1c is comparable to the drop of 0.8–1.2 percentage points typically seen when TZDs are added to insulin therapy, Dr. Rosenstock noted.
Other statistically significant changes included a 41-mg/dL drop in fasting plasma glucose with the 400-mg dose of metaglidasen, compared with placebo; reductions in uric acid of 7.5% with the 200-mg and 20% with the 400-mg doses; and dose-dependent increases in adiponectin levels, also significant for both the 200-mg and 400-mg doses. There was also a 21% reduction over placebo in triglycerides with the 400-mg dose of metaglidasen, which did not reach statistical significance due to variability but was still noteworthy, he said.
Both doses of metaglidasen were well tolerated and had no significant effect on liver or muscle enzymes, kidney function, or hematopoietic parameters.
The incidence of edema was 11% for the 200-mg dose of metaglidasen and 5.8% for the 400-mg dose, compared with 17.3% with the placebo group. Weight gains of 0.6 kg occurred in each of the two metaglidasen dose groups, compared with a 1.3-kg increase with placebo.
As expected with an insulin sensitizer, hypoglycemia was slightly higher, with episodes occurring in 37% of the 200-mg group and 36% with 400 mg, compared with 29% in the placebo group.
Metabolex is now moving forward with a second phase II study using a higher dose of metaglidasen and is actively preparing for phase III, according to a company statement.