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

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Abstract
Context: Glucagon-like peptide-1 agonists acutely lower serum glucagon. However, in the LIraglutide and Beta-cell RepAir (LIBRA) Trial, 48-week treatment with liraglutide yielded lower/unchanged fasting glucagon but, surprisingly, enhanced post-challenge glucagonemia (measured by R&D assay). Objective: Since differences between glucagon assays potentially could explain these unexpected findings, we have re-measured glucagon in all 1222 samples from this trial using the highly-sensitive/specific Mercodia assay to compare the findings between assays. Design /Setting/Participants/Intervention: 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 75g oral glucose tolerance test (OGTT) every 12 weeks (with liraglutide/placebo last administered ∼24-hours earlier). Outcome: Serum glucagon response was assessed at 0-,30-,60-,90- and 120-minutes on each OGTT, enabling determination of the area-under-the-glucagon-curve (AUCglucagon). Results: With the Mercodia assay, fasting glucagon was higher in the liraglutide arm than placebo at 12-weeks (8.5±3.4 vs. 6.4±2.3 pmol/l,p=0.01), with no between-group differences at 24-,36- and 48-weeks (all p≥0.30). Unlike the R&D findings, there was no difference in AUCglucagon between the groups at any visit (all p≥0.44). Mercodia and R&D glucagon measurements correlated at post-challenge timepoints (30-minutes: r=0.69,p<0.001; 60-minutes: r=0.76,p<0.001; 90-minutes: r=0.71,p<0.001; 120-minutes: r=0.66,p<0.001) but not at fasting (r=0.26,p=0.08). Conclusion: The Mercodia assay did not replicate the R&D glucagon findings. Though neither assay demonstrated lower post-challenge 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.

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