ESPE Yearbook of Paediatric Endocrinology

Brief summary: This phase 3 double-blind, parallel-group, randomized, placebo-controlled trial over 68 weeks randomised (2:1) 201 adolescents with obesity to receive semaglutide 2.4 mg once weekly or placebo. Both groups also received lifestyle intervention. The primary endpoint was the percentage change in BMI. Treatment with semaglutide produced clinically relevant reductions in BMI and body weight, and improvements in cardiovascular risk factors, which were all significantly greater than in the control group\.

Based on these data, semaglutide was approved by the FDA and EMA in 2023 for the treatment of obesity in adolescents aged 12 years and older.

Interestingly, the placebo-subtracted change (difference between the two groups) was greater than that achieved in the STEP1 study in adults with obesity using the same drug at the same dose (1). It is unclear why this significantly better outcome was achieved in adolescents compared to adults and gives us hope that intervention earlier in life will lead to more significant weight loss. There is also a more pronounced effect of semaglutide compared to the results of the pivotal trial of liraglutide for adolescents with obesity (2). The BMI reduction was 16.7 percentage points after 68 weeks with semaglutide once weekly compared to 4.6 percentage points after 56 weeks with liraglutide injected once daily. This corresponded to a mean weight loss of 15.3 kg on semaglutide compared to a weight gain of 2.4 kg on placebo. Although these data suggest a strong advantage of semaglutide compared to liraglutide, caution must be exercised in interpreting them, as there was no direct comparison of the two treatments in a clinical trial.

The safety profile of semaglutide was comparable to that found in adult studies (1) and was consistent with that typical of GLP-1 receptor agonists (3). Gastrointestinal side effects were the most common (62%), but did not lead to any significant study discontinuations.

The study results presented here can certainly not be generalised. The high adherence in the semaglutide group as well as in the placebo group are exceptional for obesity studies. Furthermore, significantly more female than male patients were included and in the distribution of the ethnic groups was not representative for the reference populations. Further follow-up data on the efficacy and safety of semaglutide in adolescents under real-life conditions are needed.

References: 1. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA et al.: Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021, 384(11):989–1002. 2. Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, Mastrandrea LD, Prabhu N, Arslanian S: A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med 2020, 382(22):2117–2128. 3. Lyseng-Williamson KA. Glucagon-like peptide-1 receptor analogues in type 2 diabetes: their use and differential features. Clin Drug Investig 2019, 39(8):805–819.