Effect of the GLP-1 Receptor Agonist Exenatide on Impaired Awareness of Hypoglycemia in Type 1 Diabetes: A Randomized Controlled Trial

Abstract

Context: Impaired awareness of hypoglycemia (IAH), resulting from habituation to recurrent hypoglycemia, can be reversed by strict avoidance of hypoglycemia. Adjunctive treatment with glucagon-like peptide-1 receptor agonists may reduce glucose variability, hence lower the risk of hypoglycemia and improve awareness. The aim of our study was to investigate the effect of exenatide on awareness of hypoglycemia in patients with type 1 diabetes and IAH. Methods: This was a randomized double-blind, placebo-controlled crossover trial. Ten patients with type 1 diabetes and IAH were included [age, 38.5 ± 4.4 years; 40% males; glycated hemoglobin 7.2% ± 0.4% (55.2 ± 4.8 mmol/mol)]. Patients were treated with exenatide 5 μg twice daily (first two weeks), followed by 10 μg twice daily (remaining four weeks) or matching placebo, with a four-week washout period. Patients wore blinded glucose sensors in the final weeks and modified hyperinsulinemic normoglycemic-hypoglycemic glucose clamps (nadir 2.5 mmol/L) were performed at the end of each treatment period. Results: Treatment with exenatide caused body weight to decrease compared with placebo (-3.9 ± 0.9 vs 0.6 ± 1.2 kg, P = 0.047). Exenatide did not change mean 24-hour glucose levels (8.3 ± 0.4 vs 8.5 ± 0.3 mmol/L, exenatide vs placebo, P = 0.64), median (interquartile range) percentage of time spent in hypoglycemia [15.5 (4.5, 25.5) vs 7.8 (4.4, 17.1)%, P = 0.11] and frequency of hypoglycemia (15.8 ± 3.7 vs 12.1 ± 3.5, P = 0.19). Symptom scores in response to clamped hypoglycemia were similar between exenatide [median change 1.0 (-1.5, 7.0)] and placebo [4.5 (1.5, 5.8), P = 0.08]. Conclusions: Six weeks of treatment with exenatide did not improve awareness of hypoglycemia in patients with type 1 diabetes and IAH.