Current and forthcoming pharmacotherapies for adolescent obesity: Evidence-based review

Table 1 Comparative efficacy of pharmacotherapies for adolescent obesity, ranked by magnitude of body mass index reduction

Drug (class)	Mechanism of action	Efficacy (key data)	Additional comments and comparisons	Ref.
General obesity indications (ranked by potency)
Semaglutide (GLP-1 agonist)	GLP-1 agonist (weekly). Increases satiety, reduces gastric emptying	BMI reduction: Approximately 16%-17% (vs placebo). Weight loss ≥ 5%: 73% of patients. Weight loss ≥ 20%: 37% of patients	Superior to liraglutide and exenatide in reducing BMI-SDS. Greater likelihood of achieving weight loss	[20,24]
Phentermine/topiramate (combination)	Sympathomimetic + GABA modulator. Central appetite suppression	BMI reduction: Approximately 10.4% (high dose vs placebo) to approximately 7.5% (real world). Weight loss ≥ 5%: Approximately 47% of patients	Efficacy comparable to semaglutide in some models, superior to liraglutide and orlistat. High-potency oral alternative, superior to Liraglutide, but with a higher safety monitoring burden	[28,58]
Liraglutide (GLP-1 agonist)	GLP-1 agonist (daily)	BMI-SDS reduction: -0.23 (vs placebo, common obesity), -0.34 (T2D). ≥ 5% BMI reduction: 43.3% of patients. ≥ 10% BMI reduction: 26.1%	Effective vs placebo, but inferior to semaglutide and Fen/Top in indirect comparisons. MD Weight: Approximately -5.6% vs placebo	[17,59,60]
Exenatide (GLP-1 RA)	GLP-1 agonist (weekly/daily)	BMI reduction: Between -1.1 and -1.7 points vs placebo. Main benefit in glycemic control	Inferior to semaglutide and liraglutide in terms of pure weight loss. Considered a second-line treatment	[61-63]
Orlistat (lipase inhibitor)	Blocks intestinal fat absorption (approximately 30%).	BMI reduction: -0.55 kg/m2 vs placebo. No statistically significant difference between orlistat and placebo was also documented	Lower efficacy compared to all modern agents. High dropout rate. Recent meta-analyses show inconsistent short- and long-term results in BMI reduction	[64-66]
Precision medicine (genetic/syndromic indications)
Setmelanotide (MC4R agonist)	MC4R agonist. Restores satiety pathway in genetic defects	POMC/LEPR deficiency: Massive reduction (approximately 42 points in BMI percentage of the 95th percentile). BBS: Moderate-high reduction (approximately 9.5% BMI)	Not comparable in general NMA. Exclusive gold standard for monogenic/syndromic obesity (BBS, POMC, LEPR). Key effect: Significant reduction in hunger score (hyperphagia) in > 60% of patients	[32,35]

GLP-1: Glucagon-like peptide-1; BMI: Body mass index; SDS: Standard deviation score; GABA: Gamma-aminobutyric acid; T2D: Type 2 diabetes; MD: Mean difference; RA: Receptor agonist; MC4R: Melanocortin 4 receptor; POMC: Proopiomelanocortin; LEPR: Leptin receptor; BBS: Bardet-Biedl syndrome; NMA: Network meta-analysis.