Mealtime glucose regulation with nateglinide in healthy volunteers - Comparison with repaglinide and placebo

OBJECTIVE - This study was designed to compare the pharmacodynamic effects of sing,le doses of nateglinide (A-4166), repaglinide, and placebo on mealt ime insulin secretion and glycemic control in healthy subjects. RESEARCH DESIGN AND METHODS - Fifteen healthy volunteers participated in th is open-label five-period crossover study. They received single 10-min prep randial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were perf ormed from 0 to 12 h postdose. RESULTS - Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insuli n rise of 2.3, 1.3, 1.15, and 0.8 muU.ml(-1).min(-1), respectively, over th e 0- to 30-min postmeal interval. After peaking, insulin concentrations dec reased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations w ere delayed and returned to baseline more slowly than with nateglinide trea tment. Nateglinide treatment produced lower average plasma glucose concentr ations in the 0- to 2-h postdose interval than either dose of repaglinide a nd placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose co ncentrations returned more rapidly to predose levels with nateglinide treat ment than with either dose of repaglinide. Treatment with repaglinide produ ced a sustained hypoglycemic effect up to 6 h postdose. CONCLUSIONS - In this single-dose study in nondiabetic volunteers, nateglin ide provided a more rapid and shorter-lived stimulation of insulin secretio n than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more ph ysiological insulin secretory response with the potential for a reduced ris k of postabsorptive hypoglycemia.