The acute effect of sulfonylurea drugs during long-term treatment was evaluated in two separate studies. In the first study, the levels of plasma glucose, insulin, and C-peptide were measured after intake of 10 mg glyburide alone or together with a standardized mixed meal in 10 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with 10-20 mg glyburide/day for greater than 2 yr. There was no acute effect of glyburide on the insulin and C-peptide responses to the meal or during continued fasting, indicating the absence of an acute insulinotropic action of glyburide during chronic treatment. The glucose increase after the meal was also unchanged, but a significant glucose reduction was found after glyburide intake during continued fasting, suggesting a sustained acute extrapancreatic (hepatic) effect. In the second study, the diurnal glycemic excursions in 8 NIDDM patients chronically and continuously (24 h/day) exposed to glipizide (2.5-7.5 mg 3 times/day) were similar when the drug was taken 30 min before each of the three main meals and when taken immediately before the meals. It is concluded that there is no acute insulinotropic action of sulfonylurea drugs during chronic continuous exposure, whereas an acute extrapancreatic action may prevail. During such exposure, there seems to be no clinical benefit in taking a sulfonylurea 30 min before rather than at the start of a meal.