Hypoglycemia Abrogates the Vascular Endothelial Protective Effect of Exenatide in Type 2 Diabetes Mellitus

Glucagon-like peptide-1 (GLP-1) receptor agonists improve postprandial glucose, lipid metabolism, and vascular endothelial function. However, little is known about the effect of hypoglycemia on vascular endothelial function in patients on GLP-1 receptor agonist therapy. The aim of the present study was to determine the effect of hypoglycemia on vascular endothelial function in patients with type 2 diabetes mellitus (T2DM) treated with exenatide. Seventeen patients with T2DM underwent a meal tolerance test to examine the changes in vascular endothelial function and in glucose metabolism, both without exenatide and after a single subcutaneous injection of 10 μg exenatide. Vascular endothelial function was evaluated using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide test. The results were analyzed in relation to the presence of absence of hypoglycemia. The natural logarithmically scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. Administration of exenatide caused symptomatic hypoglycemia in two patients during the meal tolerance test. The difference in the change in L_RHI was 0.125 ± 0.085 in the non-hypoglycemic group, whereas it was lower, - 0.487 ± 0.061, in the hypoglycemic group. The results of this study also suggest that the presence of hypoglycemia induces vascular endothelial dysfunction even during GLP-1 receptor agonist therapy.Trial registration: UMIN000015699.