Endocrine Abstracts

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become a popular tool for the treatment of type 2 diabetes. Unlike many other antidiabetic drug classes, distinct GLP-1 RAs have different therapeutic profiles, mostly due to their different pharmacokinetic properties. Animal experiments and human data indicate that tolerance develops toward at least some of their effects, e.g., gastric motility. Whether tolerance develops toward the glucose-lowering effect of GLP-1 receptor agonists has never been formally tested. We have conducted a series of experiments in mice and a pilot clinical trial in healthy volunteers to address the hypothesis of tolerance development.

Methods: Male C57Bl/6J mice were used. Liraglutide (600 μg/kg once a day s.c.) or exenatide (10 μg/kg twice a day s.c.) were given for 11 days (subchronic group) or 18 days (chronic group). Treatment effects on nonfasting glucose level and during the glucose tolerance test (GTT) were evaluated. Ten healthy volunteers were treated with 0.6 mg liraglutide s.c. once daily for 21 days. The drug’s effect was quantified by serial graded glucose infusion tests, with glucose and c-peptide measured every 20 min and insulin secretion rate calculated.

Results (Mice): The effect of liraglutide on nonfasting glucose was clearly weaker after chronic administration, compared to acute administration (P<0.01 Duncan’s post hoc test) while exenatide remained equally effective. During the GTT both liraglutide and exenatide, decreased AUC for glucose significantly more after acute administration compared to the chronic groups (P<0.05). Moreover, in the experiment with liraglutide the change in insulin-to-glucose ratio was significantly blunted after subchronic (P<0.05) and chronic treatment (P<0.01) compared to acute effect. Humans: (will be revealed during the presentation).

Conclusions: Prolonged treatment with exenatide and liraglutide induced tolerance in mice.