Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis.

Kailei Nong, Qingyang Shi, Xinran Xie, Yang Wang, Arnav Agarwal, Gordon H Guyatt, Haojie Zhang, Yiyuan Gao, Kamlesh Khunti, Carel W Le Roux, Indah S Widyahening, Qinlin Fan, Tianyou Liu, Yunhe Mao, Ivan D Florez, Heyue Du, Xiaohui Pan, Xinyu Zou, Chaoyang Wang, Xiaodong Sun, Jing Li, Qiukui Hao, Qingyi Jia, Feng Sun, Zhiming Zhu, Thomas Agoritsas, Haoming Tian, Per Olav Vandvik, Sheyu Li

Journal: BMJ (Clinical research ed.) 2026;394():e372161

PMID: 42419792

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Abstract

OBJECTIVE

To provide an up-to-date evidence summary about the comparative benefits and harms of drugs for adults with overweight or obesity to inform decision making for policymakers, payers, clinicians, and patients.

DESIGN

Systematic review and network meta-analysis of 24 outcomes using frequentist random effects models and bayesian dose-response models, the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach, and the Cochrane Risk of Bias 2 tool.

DATA SOURCES

Medline, Embase, and Cochrane Library, searched up to 12 November 2025.

STUDY SELECTION

Randomised controlled trials of 12 weeks' duration or longer comparing one or more drugs with lifestyle modification, placebo, or another drug.

RESULTS

This network meta-analysis comprised 262 trials (99 791 participants) evaluating 19 drugs with follow-up from 12 to 172 weeks. Compared with lifestyle modification alone, at one year, moderate to high certainty evidence shows substantial weight loss with tirzepatide (mean difference -14.9%, 95% confidence interval -16.0% to -13.9%), cagrilintide-semaglutide (CagriSema, -14.8%, -16.9% to -12.7%), oral semaglutide (-10.9%, -12.7% to -9.1%), orforglipron (-9.9%, -12.4% to -7.5%), subcutaneous semaglutide (-9.8%, -10.6% to -9.1%), and phentermine-topiramate (-8.1%, -9.7% to -6.5%). Emerging agents (ecnoglutide, mazdutide, retatrutide) may produce similar or greater reductions (13.1-14.6%; very low to low certainty). Moderate to high certainty evidence supports discontinuation because of adverse events to be highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide (risk ratios from 1.9 to 4.2); gastrointestinal events were most increased with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide (risk ratios from 3.1 to 4.2). Fatigue risk increased, particularly with naltrexone-bupropion (risk ratio 8.9; absolute increase 331 per 1000 people over one year), orforglipron (3.4; 100 more per 1000), and CagriSema (3.2; 92 more per 1000). Tirzepatide reduced fat mass the most (by 25.7%) but also lean mass the most (by 8.3%). Subcutaneous semaglutide was the only drug associated with reduced all cause mortality (risk ratio 0.81, 95% confidence interval 0.72 to 0.93) and myocardial infarction (0.72, 0.61 to 0.85), with these estimates largely informed by cardiovascular outcome trials in high risk populations. Subcutaneous semaglutide (0.43, 0.21 to 0.84) and tirzepatide (0.49, 0.27 to 0.88) reduced heart failure risk. No drugs convincingly reduced kidney failure or improved quality of life (43 trials with 45 663 participants) beyond established minimally important differences (all mean differences <5 points; minimally important difference 10). Except for larger weight reductions in trials with longer duration (shown for subcutaneous semaglutide), subgroup analyses for drug dosages and key patient characteristics did not identify credible differences in relative effects of treatment.

CONCLUSIONS

Obesity drugs produce variable weight loss at one year, with larger benefits generally accompanied by greater harms and discontinuation. Most agents do not improve quality of life meaningfully and few show cardiovascular benefits. Decisions in clinical practice should consider trade-offs between benefits and harms within the context of shared decision making.

SYSTEMATIC REVIEW REGISTRATION

PROSPERO CRD42024507993.

Address: Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China.; MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, China.; Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands.; Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.; MAGIC Evidence Ecosystem Foundation, Oslo, Norway.; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.; MAGIC Evidence Ecosystem Foundation, Oslo, Norway.; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.; Diabetes Research Centre, University of Leicester, Leicester, UK.; Diabetes Complications Research Centre, UCD Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland.; Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.; Department of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.; Laboratory of Anaesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anaesthesiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.; Sports Medicine Centre, West China Hospital, Sichuan University, Chengdu, China.; Department of Paediatrics, University of Antioquia, Medellin, Colombia.; Paediatric Intensive Care Unit, Clínica Las Américas-AUNA, Medellin, Colombia.; School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada.; Department of Internal Medicine, TidalHealth, Salisbury, MD, USA.; Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China.; Department of Neurology, Lehigh Valley Health Network, Allentown, PA, USA.; Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, Weifang, China.; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.; School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada.; Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China.; Department of Hypertension and Endocrinology, Daping Hospital, Centre for Hypertension and Metabolic Diseases, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing, China.; MAGIC Evidence Ecosystem Foundation, Oslo, Norway.; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.; Division of General Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland.; MAGIC Evidence Ecosystem Foundation, Oslo, Norway.; Department of Behavioural Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China [email protected].; MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, China.; MAGIC Evidence Ecosystem Foundation, Oslo, Norway.

DOI: 10.1136/bmj-2026-372161

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MeSH Terms: Humans, Obesity, Anti-Obesity Agents, Overweight, Weight Loss, Tirzepatide, Semaglutide, Randomized Controlled Trials as Topic, Adult