Tirzepatide as compared with semaglutide for the treatment of obesity

Aronne LJ; Horn DB; CW le Roux; Ho W; Falcon BL; E Gomez Valderas; Das S; Lee CJ; Glass LC; Senyucel C; Dunn JP; Investigators ST

doi:10.1530/ey.22.15.10

15.10

Prev Next

Section Contents Cite

ESPE Yearbook of Paediatric Endocrinology (2025) 22 15.10 | DOI: 10.1530/ey.22.15.10

ESPEYB25 15. Editors' Choice Obesity (3 abstracts)

15.10. Tirzepatide as compared with semaglutide for the treatment of obesity

Aronne LJ , Horn DB , le Roux CW , Ho W , Falcon BL , Gomez Valderas E , Das S , Lee CJ , Glass LC , Senyucel C , Dunn JP & Investigators ST

N Engl J Med 2025; 393:26-36. PMID: 40353578 doi: 10.1056/NEJMoa2416394

In Brief: This open-label, trial randomised 751 adults with obesity and without type 2 diabetes to receive tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. Percent weight loss was greater on tirzepatide (−20.2%; 95% confidence interval −21.4 to −19.1) than on semaglutide(−13.7%; −14.9 to −12.6). Nausea was the most common side-effect, in 44% of participants in both treatment arms, and led to treatment discontinuation in 2.7% on tirzepatide and 5.6% on semaglutide. The trial was funded by Eli Lilly, the manufacturer of tirzepatide.

Comment: Drugs that target incretin receptors have emerged as transformative treatments for obesity. The main targets are glucagon-like peptide-1 (GLP-1) receptors and glucose dependent insulinotropic polypeptide (GIP) receptors. Semaglutide is a long-acting GLP-1 receptor agonist. This trial substantiates the premise to develop tirzepatide, that dual agonism of both the GIP and GLP-1 receptors, which have both overlapping and nonoverlapping expression and function, is more effective than agonism of each receptor alone.

This ‘head-to-head’ trial of 2 highly successful drugs has been eagerly awaited. In 2024, semaglutide-based products (Wegovy, Ozempic, Rybelsus) generated approximately US $28.4 billion worldwide, compared to $16.5 billion for tirzepatide. Tirzepatide (‘Mounjaro’) has been dubbed the ‘King Kong’ of weight loss drugs. However, (like in the movie) tirzepatide faces stiff and increasing competition by new and emerging treatments. Retatrutide is a triple agonist, adding targeting of glucagon receptors to GIP and GLP-1, and has been dubbed the ‘Godzilla’ of weight-loss injections! As well as effectiveness, other new agents may bring fewer side-effects or easier oral route of administration. The prospect of such future developments is promising for our patients.