ESPE Abstracts

Introduction: When used to treat obesity, glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) improve both BMI and metabolic health. Liraglutide is approved by both the EMA and FDA for the treatment of pediatric obesity, from 12 years and older. However, 26 weeks after discontinuation of liraglutide, the weight lost during treatment is regained. Prolonged exogenous stimulation of hormone-specific receptors may influence endogenous hormonal regulation. Treatment with the GLP-1RA liraglutide has been shown to both suppress and enhance endogenous concentrations of GLP-1 in adults. It is still unknown what effects GLP-1RA have on endogenous hormonal systems in children and adolescents with obesity. If GLP-1 is suppressed, it may contribute to a more pronounced hunger after discontinuation. For these reasons, we measured the effect of the GLP-1RA exenatide on secretory patterns of endogenous intact GLP-1 as well as insulin, proinsulin, C-peptide, glicentin, glucagon and glucose in adolescents with obesity.

Method: The Combating JUvenile Diabetes and Obesity (Combat-JUDO) trial was a 6-month multi-center, randomized, double-blinded, parallel, placebo-controlled trial (clinicaltrials.gov: NCT02794402). Participants were randomized to receive either exenatide (n = 22) or placebo (n = 22) for six months. Complete sample sets were available for 19 patients in the exenatide group and 18 in the placebo group. Venous blood was collected in EDTA tubes during an oral glucose tolerance test (OGTT) at the beginning of the study and after six months of treatment. Intact endogenous GLP-1 was measured by chemiluminescent enzyme-linked assay (Mercodia, Uppsala, Sweden) which has no reported cross-reactivity with exenatide. Insulin, proinsulin, C-peptide, glicentin and glucagon were measured using ELISA (Mercodia).

Results: Basic characteristics of the participants have been published previously. There was no difference in age, BMI, sex, glycaemic status or Tanner staging between the groups. Treatment with exenatide significantly lowered glucose levels during the OGTT (P<0.0001). Insulin secretion had a later peak after treatment (60 minutes), compared to before (30 minutes). No other differences in insulin were seen during the OGTT. Fasting proinsulin (mean difference -4.961 +/- 1.409 pmol/l, P=0.0024) and the proinsulin to insulin ratio (mean difference -0.03842 +/- 0.01190, P=0.0047) were both lowered following treatment. Intact endogenous GLP-1, glucagon, glicentin and C-peptide were not affected by treatment.

Conclusion: Six months of treatment with exenatide improves glycemic control and lowers proinsulin, but does not affect endogenous GLP-1 in adolescents with obesity, making it an interesting candidate for pharmacological treatment of pediatric obesity.