Purpose To study the effect of different sulfonylureas on counterregulatory recovery from severe hypoglycemia. Severe hypoglycemia, the most serious side effect of sulfonylurea therapy, has been reported to occur more frequently with glyburide than glimepiride. Glyburide, but not glimepiride, has been reported to inhibit secretion of glucagon, the most important counterregulatory hormone.
Methods To test the hypothesis that this may be involved in the different frequency of severe hypoglycemia observed with these sulfonylureas, we performed hyperinsulinemic hypoglycemic (˜ 2.5 mM/L) clamps in 16 normal volunteers who received in randomized order placebo, glyburide (10 mg), and glimepiride (4 mg) just prior to beginning the insulin infusion and measured plasma glucagon, insulin, C-peptide, glucagon, epinephrine, cortisol and growth hormone levels during the clamp and during a three hour recovery period after discontinuation of the insulin infusion.
Results We found that neither sulfonylurea altered glucagon responses and those of other counterregulatory hormones (except cortisol) during the clamp. However, glyburide delayed plasma glucose recovery from hypoglycemia (plasma glucose at end of recovery period: control 4.9 ± 0.2 mM, glyburide 3.7 ± 0.2 mM [p = .0001] and glimepiride 4.5 ± 0.2 mM [p = .08]). Despite lower plasma glucose levels, glyburide stimulated insulin secretion during this period (0.89 ± 0.13 vs 1.47 ± 0.15 pmol kg-1 min control vs glyburide, p = .001) whereas glimepiride did not (p = .08).
Conclusion Our results indicate that acute administration of neither glyburide nor glimepiride alters glucagon responses during hypoglycemia. In contrast, during recovery from hypoglycemia glyburide but not glimepiride inappropriately stimulated insulin secretion at low plasma glucose levels. We therefore conclude that this differential effect on insulin secretion may be an important factor in explaining why glyburide causes severe hypoglycemia more frequently than glimepiride.