Effect of liraglutide vs. placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: a randomized controlled trial.

Kim, Sun H; Abbasi, Fahim; Nachmanoff, Clara; Stefanakis, Konstantinos; Kumar, Ajay; Kalra, Bhanu; Savjani, Gopal; Mantzoros, Christos S

AIMS To examine how circulating GLP-1 concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, GLP-2, glucagon, oxyntomodulin, glicentin, and major proglucagon fragment, which also regulate metabolic and weight control. MATERIALS AND METHODS Adults who were overweight/obese (BMI 27-40 kg/m2 ) with prediabetes were randomized to liraglutide (1.8mg/day) vs placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist (GLP-1A)) and endogenous (GLP-1E) GLP-1, alongside 5 other PGDP concentrations during a mixed-meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n=16; placebo, n=19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance, and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose, and levels of PGDPs. RESULTS Participants on liraglutide vs placebo had significantly (p≤0.004) decreased weight (mean -3.6%, 95% CI [-5.2, -2.1]), SSPG (-32% [-43, -22]) and glucose AUC (-7.0% [-11.5, -2.5]), and increased ISR AUC (30%, [16, 44]). Treatment with liraglutide significantly (p≤0.005) increased exogenous GLP-1A AUC (median 310 vs 262 pg/mL X 8h at baseline but decreased endogenous GLP-1E AUC (13.1 vs 24.2 pmol/L x 8h at baseline)), as well as the 5 other PGDPs. Only glucagon AUC decreased in the placebo group (471 vs 594 pg/mL x 8h at baseline). GLP-1A AUC at study end was significantly (p≤0.04) linearly associated with % decrease in weight (r=-0.54) and SSPG (r=-0.59) and increase in ISR AUC (r=0.51) in the liraglutide group. CONCLUSIONS Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action, and secretion in a linear manner. Importantly, liraglutide also downregulates all other PGDPs, normalization of the levels of which may provide additional metabolic benefits in the future. This article is protected by copyright. All rights reserved.