SAN DIEGO — The novel investigational compound sitagliptin significantly lowers glucose levels and is well tolerated in patients with type 2 diabetes, three investigators reported in separate presentations at the annual scientific sessions of the American Diabetes Association.
Sitagliptin, manufactured by Merck & Co., appears to work by inhibiting the enzyme dipeptidyl peptidase IV (DPP-IV), which inactivates the incretin gut hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The two peptides, normally released by the gut after a meal, enhance insulin secretion, while GLP-1 also inhibits glucagon secretion. Inhibition of DPP-IV activity increases the active concentration of these hormones, thereby enhancing their glucose-lowering action.
Unlike some of the new agents that mimic the action of GLP-1, sitagliptin is orally active and in these trials did not appear to be associated with increased gastrointestinal side effects, said Ronald L. Brazg, M.D., of Rainier Clinical Research Center, Renton, Wash.
Russell Scott, M.D., Ph.D., reported data from the largest of three randomized, double-blind, placebo-controlled phase II studies presented at the meeting. In the dose-finding study, 743 patients with type 2 diabetes aged 21–76 years were taken off all other medications and randomized to 5 mg, 12.5 mg, 25 mg, or 50 mg of sitagliptin twice daily; glipizide 5–20 mg twice daily; or placebo. At baseline, the subjects had a mean hemoglobin A1c level of 7.9%, with 21% having an A1c level of 7.0% or lower.
At week 12, there were statistically significant dose-dependent reductions in A1c level, compared with the placebo group, in all sitagliptin dose groups, ranging from a 0.38 percentage point drop with 5 mg twice daily to a 0.77-point drop with 50 mg twice daily. The reduction in the glipizide group—the dose was titrated up every 2 weeks as needed—was 1.0 percentage point. Similarly, 2-hour fasting plasma glucose (FPG) levels fell in a dose-dependent manner, with reductions ranging from 35.0 mg/dL to 54.2 mg/dL in the four sitagliptin groups. Glipizide reduced FPG level by 72.1 mg/dL, reported Dr. Scott, professor of medicine and director of the lipid and diabetes research group at Christchurch Hospital and School of Medicine, New Zealand.
There were no changes in weight with sitagliptin or placebo, compared with a mean 1.1-kg weight gain at week 12 with glipizide. Hypoglycemia occurred in 0%–4% of the sitagliptin groups and 2% of the placebo group, compared with 17% of those taking glipizide. Gastrointestinal adverse events occurred in 8%–17% with sitagliptin, 12% with placebo, and 14% with glipizide.
In a small second study, 28 patients who were already taking 1,500 mg/day or more of metformin were randomized to receive 50 mg of sitagliptin twice daily or placebo. The study was originally designed to have two 4-week crossover periods. However, because the patients who received sitagliptin during the first 4 weeks didn't return to baseline after the end of the second 4 weeks in which they received placebo, Dr. Brazg presented only the results from the first 4 weeks.
Over a 24-hour period, the weighted mean glucose level in the sitagliptin plus metformin group was 125 mg/dL, compared with 158 mg/dL for placebo plus metformin, a mean reduction of 33 mg/dL. The difference in FPG levels—128 vs. 149 mg/dL—also was highly significant, even though those values were not markedly elevated to begin with.
There were no clinically meaningful changes in body weight, in hepatic or muscle enzymes, or in any laboratory parameters, he said.
The third study was presented in a poster by Gary Herman, M.D., of Merck Research Laboratories, Rahway, N.J., and his associates. Here, 552 patients aged 30–74 years with a mean baseline A1c level of 5.8%–10.4% (29% had levels of 7% or less) and mean FPG level of 130 mg/dL or higher were randomized to sitagliptin 25 mg, 50 mg, or 100 mg once daily; sitagliptin 50 mg twice daily; or placebo. Patients who had been taking other oral hypoglycemics underwent a washout period.
At week 12, there were significant mean reductions in A1c level in all treatment groups, compared with the placebo group, ranging from 0.39 percentage points for 25 mg twice daily to 0.56 points for 100 mg once daily.
In an analysis with the last observation carried forward, the differences were greatest in those with the highest A1c levels at baseline, with a reduction of 0.82 percentage points with the 100 mg/day dose for those with baseline A1c values of 8.5% or higher, compared with a 0.37-point drop among those who started out at less than 7%. Similarly, reductions in FPG level, compared with placebo, ranged from 11.0 mg/dL with 25 mg twice daily to 17.2 mg/dL with 100 mg once daily, Dr. Herman and his associates reported.