Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUCGLP-1 at 12 weeks ( P  < .001), 24 weeks ( P  < .001), 36 weeks ( P  = .03) and 48 weeks ( P  = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology.