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Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

BMJ 2023; 381 doi: https://doi.org/10.1136/bmj-2022-074068 (Published 06 April 2023) Cite this as: BMJ 2023;381:e074068
  1. Qingyang Shi, research fellow1,
  2. Kailei Nong, master student1,
  3. Per Olav Vandvik, professor2,
  4. Gordon H Guyatt, professor3,
  5. Oliver Schnell, professor4,
  6. Lars Rydén, professor5,
  7. Nikolaus Marx, professor6,
  8. Frank C Brosius III, professor7,
  9. Reem A Mustafa, nephrologist8,
  10. Arnav Agarwal, internist3 9,
  11. Xinyu Zou, masters student1,
  12. Yunhe Mao, doctoral student10,
  13. Aminreza Asadollahifar, methodologist11,
  14. Saifur Rahman Chowdhury, methodologist3,
  15. Chunjuan Zhai, cardiologist12,
  16. Sana Gupta, methodologist3,
  17. Ya Gao, methodologist3 13,
  18. João Pedro Lima, methodologist3,
  19. Kenji Numata, methodologist14,
  20. Zhi Qiao, medical student15,
  21. Qinlin Fan, masters student1,
  22. Qinbo Yang, doctoral student16,
  23. Yinghui Jin, methodologist17,
  24. Long Ge, professor18,
  25. Qiuyu Yang, master student19,
  26. Hongfei Zhu, master student20,
  27. Fan Yang, endocrinologist21,
  28. Zhe Chen, doctoral student22,
  29. Xi Lu, master student1,
  30. Siyu He, medical student23,
  31. Xiangyang Chen, endocrinologist24,
  32. Xiafei Lyu, radiologist25,
  33. Xingxing An, endocrinologist1,
  34. Yaolong Chen, professor18,
  35. Qiukui Hao, geriatrician26,
  36. Eberhard Standl, professor4,
  37. Reed Siemieniuk, methodologist3,
  38. Thomas Agoritsas, professor3 27,
  39. Haoming Tian, professor1,
  40. Sheyu Li, endocrinologist1
  1. 1Department of Endocrinology and Metabolism, Division of Guideline and Rapid Recommendation, Cochrane China Centre, MAGIC China Centre, Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Chengdu, China
  2. 2Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway
  3. 3Department of Health Research Methods, Evidence and Impact, McMaster University, ON, Canada
  4. 4Forschergruppe Diabetes eV at the Helmholtz Centre, Munich-Neuherberg, Germany
  5. 5Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden
  6. 6Clinic for Cardiology, Angiology, and Intensive Care Medicine, RWTH Aachen University, University Hospital Aachen, Aachen, Germany
  7. 7Division of Nephrology, University of Arizona College of Medicine Tucson, Tucson, AZ, USA
  8. 8Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas, Kansas City, MI, USA
  9. 9Department of Medicine, McMaster University, Hamilton, ON, Canada
  10. 10Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
  11. 11Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  12. 12Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
  13. 13Evidence-Based Medicine Centre, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
  14. 14Department of Emergency Medicine, St Marianna University School of Medicine, Kawasaki, Japan
  15. 15West China School of Medicine, Sichuan University, Chengdu, China
  16. 16Department of Nephrology, National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  17. 17Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
  18. 18Evidence-Based Social Science Research Centre, School of Public Health, Lanzhou University, Lanzhou, China
  19. 19Evidence-Based Nursing Centre, School of Nursing, Lanzhou University, Lanzhou, China
  20. 20Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, China
  21. 21Department of Endocrinology and Metabolism, Chengdu Fifth People’s Hospital, Chengdu, China
  22. 22Evidence-Based Medicine Centre, Tianjin University of Traditional Chinese Medicine, Tianjin, China
  23. 23Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
  24. 24Department of Endocrinology and Metabolism, First People’s Hospital of Shuangliu District, Chengdu, China
  25. 25Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
  26. 26School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada
  27. 27Division of General Internal Medicine, Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  1. Correspondence to: S Li lisheyu{at}gmail.com (or @LisheyuSheyu on Twitter)
  • Accepted 1 March 2023

Abstract

Objective To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options.

Design Systematic review and network meta-analysis.

Data sources Ovid Medline, Embase, and Cochrane Central up to 14 October 2022.

Eligibility criteria for selecting studies Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach.

Results The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference −8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes).

Conclusions This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.

Systematic review registration PROSPERO CRD42022325948.

Footnotes

  • Contributors: QS and KNo contributed equally to this study. QS, SL, POV, GHG, OS, FCB, LR, NM, ES, QH, RAM, RS, TA, and HT conceived and designed the study. SL, POV, GHG, OS, FCB, LR, NM, ES, QH, RAM, AAg, and HT discussed and drafted the study protocol. QS, KNo, QF, ZQ, and FY screened and selected the articles. QS, KNo, YM, QF, ZQ, XZ, XC, ZC, XL, and SH extracted the data. QS, KNo, LG, YJ, YM, AAs, CZ, JPL, KNu, SRC, SG, YG, HZ, QiuY, XL, QinY, and XA assessed the risk of bias of included trials. QS analysed the data. QS, KNo, SL, and GHG rated and revised the GRADE certainty of evidence. QS, SL, POV, GHG, OS, FCB, LR, NM, ES, RAM, AAg, RS, YC, and TA interpreted the results. QS, SL, and GHG drafted the manuscript. QS, SL, GHG, POV, OS, FCB, LR, NM, ES, RAM, and AAg critically revised the manuscript. All authors contributed to revising the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. SL, POV, GHG, OS, FCB, LR, NM, ES, QH, RAM, RS, TA, and HT supervised the study. SL is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This study is supported by the Sichuan Science and Technology Programme (grant 2022YFH0114) and 1.3.5 Clinical Research Incubation Project, West China Hospital, Sichuan University (grant 2020HXF011). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from Sichuan Science and Technology Bureau and West China Hospital, Sichuan University for the submitted work; QS, KNo, POV, AAg, TA, RS, QH, QF, ZQ, FY, XZ, XC, YJ, LG, YM, QinY, AAs, CZ, JPL, KNu, SRC, SG, YG, XL, QiuY, HZ, XA, ZC, XL, SH, YC, HT, and GHG received no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. ES reported personal fees from Oxford Diabetes Trials Unit, Bayer, Berlin Chemie, Boehringer Ingelheim, Menarini, Merck Serono, EXCEMED, Novartis, Novo Nordisk, and Sanofi. LR reported grants or contracts from Swedish Heart Lung Foundation, Stockholm County Council, Erling Perssons Foundation, and Boehringer-Ingelheim, and payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer AG, Boehringer Ingelheim, and Novo Nordisk. FCB reported grants or contracts from National Institutes of Health, and consulting fees from Gilead Sciences. RAM reported grants or contracts from Boehringer Ingelheim. OS reported payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott Diagnostics, Lilly Deutschland, Boehringer Ingelheim, Bayer, Mannkind, and Lifescan and is a founder and CEO of Sciarc GmbH. NM reported grants or contracts from Boehringer Ingelheim, Merck, Novo Nordisk, Deutsche Forschungsgesellschaft (German Research Foundation; TRR 219), and consulting fees from Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, BMS, and payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and AstraZeneca. SL received the fund from the Sichuan Science and Technology Programme and West China Hospital of Sichuan University.

  • The manuscript’s guarantors (SL) affirm that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

  • Dissemination to participants and related patient and public communities: This study will support the update of a BMJ Rapid Recommendation (https://www.bmj.com/rapid-recommendations).

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

No additional data available.

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