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Peer-reviewedCC BY-NCBMJ

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

  • Kailei Nong1,2
  • Qingyang Shi3
  • Xinran Xie1,2
  • Yang Wang4
  • Arnav Agarwal5,6,7
  • Gordon H Guyatt5,7
  • Haojie Zhang1,2
  • Yiyuan Gao1,2
  • Kamlesh K. Khunti8
  • Carel Wynand le Roux9
  • Indah Suci Widyahening10
  • Qinlin Fan1,2
17 more authors
  • Tianyou Liu11,12
  • Yunhe Mao13
  • Iván D. Flórez14,15,16
  • Heyue Du17
  • Xiaohui Pan1
  • Xinyu Zou1,2
  • Chaoyang Wang18
  • Xiaodong Sun19
  • Jing Li1
  • Qiukui Hao5,16
  • Qingyi Jia1
  • Feng Sun20
  • Zhiming Zhu21
  • Thomas Agoritsas5,22,7
  • Haoming Tian1
  • Per Olav Vandvik23,7
  • Sheyu Li1,2,7
23 affiliations
  1. 1Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
  2. 2MAGIC China Centre, Cochrane China Centre, Chinese Evidence-based Medicine, West China Hospital, Sichuan University, Chengdu, China
  3. 3Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands
  4. 4Department 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
  5. 5Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada
  6. 6Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  7. 7MAGIC Evidence Ecosystem Foundation, Oslo, Norway
  8. 8Diabetes Research Centre, University of Leicester, Leicester, UK
  9. 9Diabetes Complications Research Centre, UCD Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland
  10. 10Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
  11. 11Department of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  12. 12Laboratory 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
  13. 13Sports Medicine Centre, West China Hospital, Sichuan University, Chengdu, China
  14. 14Department of Paediatrics, University of Antioquia, Medellin, Colombia
  15. 15Paediatric Intensive Care Unit, Clínica Las Américas-AUNA, Medellin, Colombia
  16. 16School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada
  17. 17Department of Internal Medicine, TidalHealth, Salisbury, MD, USA
  18. 18Department of Neurology, Lehigh Valley Health Network, Allentown, PA, USA
  19. 19Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, Weifang, China
  20. 20Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
  21. 21Department of Hypertension and Endocrinology, Daping Hospital, Centre for Hypertension and Metabolic Diseases, Army Medical University of PLA, Chongqing Institute of Hypertension, Chongqing, China
  22. 22Division of General Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland
  23. 23Department of Behavioural Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
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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.

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Cite

BibTeXRIS
BibTeX
@article{nong2026comparative,
  title = {{Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis}},
  author = {Kailei Nong and Qingyang Shi and Xinran Xie and Yang Wang and Arnav Agarwal and Gordon H Guyatt and Haojie Zhang and Yiyuan Gao and Kamlesh K. Khunti and Carel Wynand le Roux and Indah Suci Widyahening and Qinlin Fan and Tianyou Liu and Yunhe Mao and Iván D. Flórez and Heyue Du and Xiaohui Pan and Xinyu Zou and Chaoyang Wang and Xiaodong Sun and Jing Li and Qiukui Hao and Qingyi Jia and Feng Sun and Zhiming Zhu and Thomas Agoritsas and Haoming Tian and Per Olav Vandvik and Sheyu Li},
  journal = {BMJ},
  year = {2026},
  month = jul,
  doi = {10.1136/bmj-2026-372161},
  url = {https://doi.org/10.1136/bmj-2026-372161},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis
AU  - Kailei Nong
AU  - Qingyang Shi
AU  - Xinran Xie
AU  - Yang Wang
AU  - Arnav Agarwal
AU  - Gordon H Guyatt
AU  - Haojie Zhang
AU  - Yiyuan Gao
AU  - Kamlesh K. Khunti
AU  - Carel Wynand le Roux
AU  - Indah Suci Widyahening
AU  - Qinlin Fan
AU  - Tianyou Liu
AU  - Yunhe Mao
AU  - Iván D. Flórez
AU  - Heyue Du
AU  - Xiaohui Pan
AU  - Xinyu Zou
AU  - Chaoyang Wang
AU  - Xiaodong Sun
AU  - Jing Li
AU  - Qiukui Hao
AU  - Qingyi Jia
AU  - Feng Sun
AU  - Zhiming Zhu
AU  - Thomas Agoritsas
AU  - Haoming Tian
AU  - Per Olav Vandvik
AU  - Sheyu Li
PY  - 2026
DA  - 2026/07/08
JO  - BMJ
DO  - 10.1136/bmj-2026-372161
UR  - https://doi.org/10.1136/bmj-2026-372161
AB  - 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.
SN  - 1756-1833
ER  -