A Phase 3 Randomized Clinical Trial Using A Once-Weekly Glucagon-Like Peptide-1 Receptor Agonist In Adolescents And Young Adults With Hypothalamic Obesity

Aim To evaluate the efficacy, safety and tolerability of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with hypothalamic obesity (HO).Materials and Methods A two-arm, randomized, multicentre, double-blind, placebo-controlled trial was conducted in 10- to 25-year-olds with hypothalamic injury following intracranial tumour and HO. Participants were randomized to once-weekly subcutaneous injections of a GLP-1 RA exenatide 2 mg (ExQW) or placebo for 36 weeks. The primary efficacy endpoint was 36-week % change in body mass index (BMI). Secondary outcomes included change in body composition (by dual energy x-ray absorptiometry).Results Forty-two participants were randomized to ExQW (n = 23) or placebo (n = 19). Participants were 5 +/- 2 years (mean +/- SD) postdiagnosis and development of HO (BMI 37.3 +/- 7.1 kg/m(2)). In intention-to-treat analysis, the effect of 36-week ExQW vs. placebo on % Delta BMI was not significant (estimated treatment difference -1.7 +/- 1.8%, 95% CI -4.1 to 0.6%, P = .40); however, total body fat mass was reduced (estimated treatment difference -3.1 +/- 1.4 kg, 95% CI -5.7 to -0.4 kg, P = .02). There was a significant reduction in waist circumference (estimated effect of treatment -3.5 [95% CI -5.5 to -1.6] cm, P = .004). All patients treated with placebo increased % of adipose tissue, while 50% treated with ExQW had reductions (P < .001). Mean HbA1c, glucose tolerance and serum lipids did not change significantly with therapy. ExQW was well tolerated. The most frequent adverse events were transient gastrointestinal disturbances (ExQW vs. placebo: nausea 6/23 vs. 3/18, vomiting 4/23 vs. 4/18 and diarrhoea 7/23 vs. 3/18).Conclusions GLP-1 RAs are a promising and safe treatment to improve or stabilize HO in children and young adults.