Impact of the Glucagon Assay When Assessing the Effect of Chronic Liraglutide Therapy on Glucagon Secretion.

Abstract

Glucagon-like peptide-1 agonists acutely lower serum glucagon. However, in the Liraglutide and β-Cell Repair (LIBRA) Trial, 48-week treatment with liraglutide yielded lower/unchanged fasting glucagon but, surprisingly, enhanced postchallenge glucagonemia [measured by R&D Systems (Minneapolis, MN) assay]. Because differences between glucagon assays potentially could explain these unexpected findings, we have remeasured glucagon in all 1222 samples from this trial using the highly-sensitive/specific Mercodia assay to compare the findings between assays. In LIBRA, 51 patients 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 serial oral glucose tolerance test (OGTT) every 12 weeks (with liraglutide/placebo last administered ∼24 hours earlier). Serum glucagon was measured every 30 minutes on each OGTT, enabling determination of the area under the glucagon curve (AUCglucagon). With the Mercodia assay, fasting glucagon was higher in the liraglutide arm than placebo at 12 weeks (P = 0.01), with no between-group differences at 24, 36, and 48 weeks. There was no difference in AUCglucagon between the groups at any visit. Mercodia and R&D Systems glucagon measurements correlated at postchallenge time points but not at fasting. The Mercodia assay did not replicate the R&D Systems glucagon findings. Although neither assay demonstrated lower postchallenge glucagonemia with chronic liraglutide last administered ∼24 hours earlier, the differential response reported by these assays precludes definitive conclusion and highlights the critical role of assay selection when measuring glucagon in clinical studies.