Tolerance Does Not Develop Toward Liraglutide's Glucose-Lowering Effect.

Abstract

Glucagon-like peptide-1 receptor agonists are popular antidiabetic drugs with potent glucose-lowering effects and low risk of hypoglycemia. 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 glucagon-like peptide-1 receptor agonists has never been formally tested. The objective of this pilot study was to test the hypothesis whether tolerance develops toward glucagon-like peptide-1 receptor agonists' glucose-lowering effect in chronic use. We conducted a single group, open-label clinical trial. Ten healthy volunteers were treated with 0.6 mg liraglutide once daily subcutaneously for 21 days. The drug's effect was quantified by serial graded glucose infusion tests, with glucose and c-peptide measured every 20 minutes and insulin secretion rate calculated. The primary outcome was a change in the dose-response relationship between calculated insulin secretion rate and blood glucose level after acute and chronic administration of liraglutide. Liraglutide clearly decreased the glucose values during the graded glucose infusion test and robustly enhanced insulin secretion. For all parameters, chronic liraglutide was as effective as acute treatment in human subjects. We conclude that our results largely refute the hypothesis of tolerance development with prolonged liraglutide use in healthy nonobese humans.