This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

A.C. has received speaking fees from Astra Zeneca, Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Sanofi, Menarini; research grants from Eli Lilly, Novo Nordisk and Menarini; and is a member of the data monitoring committee of Boehringer Ingelheim, co-chair of the obesity management working group of EASO. J.L.B. Advisory board member for Novo Nordisk (all fees paid to institution); representative of EASO on a Regeneron council (volunteer, no fees); speaker honoraria for participation in sponsored scientific sessions (all fees paid to institution); President-Elect of EASO. A.B. has received payment of honoraria from Astra Zeneca, Servier, Novo Nordisk, Eli Lilly and Novartis as speaker and/or member of advisory boards; Secretary of the Croatian Society of Obesity EASO ECN Board (Middle region), EASO COMs Working Group L.B. has payment of honoraria from Amgen, Boehringer Ingelheim, Bruno Farmaceutici, Eli-Lilly, Novo Nordisk, Pfizer, Recordati, Regeneron and Roche; speaker fees or educational activities from Pronokal and Rhythm Pharmaceuticals; Vice President Southern Region of EASO, member of the Standing Expert Panel for the endocrine-metabolic area of the National Guidelines System of the Italian Institute of Health (Istituto Superiore di Sanita). D.D. has received speaker and advisory board fees from Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Astra Zeneca and research grants from Eli Lilly, Novo Nordisk and Boehringer Ingelheim. L.F. has received speaker and/or advisory fees from Novo Nordisk, Eli-Lilly, Zentiva, Stada, Vice-president Middle Region of EASO G.F. has received payment of honoraria from Eli Lilly, Novo Nordisk, Regeneron, Astra Zeneca and Marabou Foundation as speaker and/or member of advisory boards, and payment of honoraria as member of the OPEN Spain Initiative. G.G. has received research funding from Novo Nordisk, payment of honoraria as speaker (company educational seminars) from Novo Nordisk and Eli Lilly, and as Advisory Board member for Novo Nordisk (all fees paid to institution); co-chair of Basic and Discovery Science Working Group of EASO. J.G. is a shareholder of Elevate Access Ltd, which has received research and educational funding, including from the EASO. M.M. received speaking fees from Novo Nordisk and Eli Lilly, and consultancy fees from Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. P.S. received payment of honoraria and consulting fees from Boehringer Ingelheim, Chiesi, Novo Nordisk, Eli Lilly, Pfizer, and Roche as a member of advisory boards. B.M.-T. has received grants from the EASO New Clinical Investigator Award 2024 and the EFSD Rising Star 2024, both supported by the Novo Nordisk Foundation. Matteo Monami has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb. V.Y. was engaged in advisory boards and lectures with Novo Nordisk, Eli Lilly, Rhythm and Regeneron; President of EASO. B.M. has received speaker and/or advisory fees from Novo Nordisk, Eli-Lilly, Astra Zeneca, Janssen, Pfizer, MSD and a research grant from Novo Nordisk; and is a shareholder of Reset Health.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This is data from randomized clinical trial already published

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data available upon request to the corresponding authors