Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial

Abstract

Aim: To examine how circulating glucagon-like peptide-1 (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, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control.

Materials and methods: Adults who were overweight/obese (body mass index 27-40 kg/m² ) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and endogenous (GLP-1E) GLP-1, alongside five 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 versus placebo had significantly (P ≤ .004) decreased weight (mean -3.6%, 95% CI [-5.2% to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was significantly (P ≤ .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. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP-1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP-1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to decrease their endogenous production in contrast to weight loss-dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells.

Conclusions: Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.

Keywords: clinical trial, control, GLP-1, GLP-1 analogue, glucagon, glycaemic, liraglutide.

Figure 1:. Exogenous and endogenous GLP-1 levels at baseline and 14 weeks of liraglutide vs placebo administration.

MMTT curves at baseline (solid circles) and 14 weeks (open circles) for GLP-1A and GLP-1E in participants receiving placebo (n=19, A and C) or liraglutide (n=16, B and D respectively). * represents p<0.05 at each particular time point using paired t-test. p for AUCs = statistical difference betweenbaseline and 14-week AUCs using paired t test. Arrows represent meals administered during the MMTT. Data presented in mean ± SEM (error bars).

Figure 2:. MMTT concentrations of glucose, GLP-2, and oxyntomodulin.

MMTT curves at baseline (solid circles) and 14 weeks (open circles) for glucose, GLP-2, and oxyntomodulin in participants receiving placebo (n=19, A, C, E) or liraglutide (n=16, B, D, F respectively). * represents p<0.05 at each particular time point using paired t-test. p for AUCs = statistical difference between baseline and 14-week AUCs using paired t test. Arrows represent meals administered during the MMTT. Data presented in mean ± SEM (error bars).

Figure 3:. MMTT concentrations of glicentin, glucagon, and MPGF.

MMTT curves at baseline (solid circles) and 14 weeks (open circles) for glicentin, glucagon, and MPGF in participants receiving placebo (n=19, A, C, E) or liraglutide (n=16, B, D, F respectively). * represents p<0.05 at each particular time point using paired t-test. p for AUCs = statistical difference between baseline and 14-week AUCs using paired t test. Arrows represent meals administered during the MMTT. Data presented in mean ± SEM (error bars).

Figure 4:. Relationship between GLP-1A AUC and percentage change in weight, insulin resistance (SSPG), and ISR after liraglutide vs placebo administration.

Data are shown for % change in weight, SSPG, and ISR at 14 weeks relative to baseline in participants receiving placebo (n=19, A, C, E) or liraglutide (n=16, B, D, F respectively). r for Spearman correlation coefficient, p represents significance for correlation between GLP-1A and percentage change.