Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus

Objectives: Pharmacodynamic effects of nateglinide, a novel antidiabetic agent, were investigated in patients with type-2 diabetes mellitus. Methods: Ten patients participated in this single-center, double-blind, crossover study. Plasma glucose and insulin levels were measured over 24 h following five 7-day treatment periods with nateglinide (30, 60, or 120 mg) or placebo given three times daily before breakfast, lunch, and dinner. A fifth treatment consisted of 120 mg nateglinide four times daily, with the fourth dose given before an evening snack. Results: Taken 10 min before meals, doses of 30-120 mg nateglinide caused dose-dependent increases in plasma insulin levels that were significantly greater than with placebo. Higher doses were more effective and had a longer duration of action than lower doses. Nateglinide was also significantly better than placebo in lowering plasma glucose levels; the 60-mg and 120-mg doses were similarly effective and superior to the 30-mg nateglinide treatment. Following the fourth 120-mg dose, the glucose-lowering effects of treatment were maintained through the night. No serious adverse events occurred during the study. There were no events of hypoglycemia and no clinically meaningful changes in safety parameters. Conclusions: Nateglinide produced rapid, short-lived, dose-related increases in plasma insulin that significantly lowered mealtime glucose excursions compared with placebo with no incidence of hypoglycemia. The decrease in mealtime glucose levels produced a significant improvement in overall 24-h glycemia.