Counterregulatory Responses to Hypoglycemia Differ Between Glimepiride and Glyburide in Non Diabetic Individuals

Objective. Reported rates of hypoglycemia in patients with type 2 diabetes mellitus are lower with glimepiride as compared to glyburide. The aim of this study was to determine whether physiologic differences in counterregulatory neuroendocrine and metabolic mechanisms during hypoglycemia provide a basis for the observed clinical differences between glimepiride and glyburide. Research design and methods. Non-diabetic volunteers (age 38 +/- 2 years, BMI 26 +/- 1 kg/m(2)) were studied in a single-blind fashion during separate 2 day randomized protocols consisting of 2 h hyperinsulinemic (9 pmol/kg/min) euglycemic (4.9 +/- 0.1 mmol) and hypoglycemic (2.9 +/- 0.1 mmol/L) clamps. Individuals received biologically equivalent doses of glimepiride (4 mg) or glyburide (10 mg) 1 h prior to each glucose clamp (n = 11) as well as a control group of placebo studies. Glucose kinetics were calculated using D-Glucose-6-6d(2). Results. Insulin and C-peptide levels were increased (p < 0.05) during euglycemia in both sulfonylurea groups as compared to placebo. However, despite equivalent hypoglycemia, insulin and C-peptide levels were higher (p < 0.05) only after glyburide. Glucagon responses and endogenous glucose production (EGP) were decreased (p < 0.05) during hypoglycemia following glyburide administration as compared to glimepiride. Glyburide reduced (p < 0.05) norepinephrine responses during euglycemic clamps. In addition combined epinephrine and norepinephrine responses during hypoglycemia were reduced (p < 0.05) following glyburide as compared to placebo. Leptin levels fell by a greater amount (p < 0.05) during hypoglycemia with both sulfonylureas as compared to placebo. Conclusions. In summary, glimepiride and glyburide can both similarly increase insulin and C-peptide levels during hyperinsulinemic euglycemia. However, during moderate hyperinsulinemic hypoglycemia (2.9 mmol/L) glyburide resulted in increased C-peptide and insulin, but blunted glucagon, sympathetic nervous system and EGP responses. We conclude that glyburide can acutely reduce key neuroendocrine and metabolic counterregulatory defenses during hypoglycemia in healthy individuals. (C) 2015 Elsevier Inc. All rights reserved.