Efficacy and Safety of Once-Weekly Subcutaneous Semaglutide in Overweight or Obese Adults: A Systematic Review with Meta-Analysis

Abstract

Background To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide treatment in overweight or obese patients without type 2 diabetes.

Methods Randomized clinical trials that assessed the impact of once-weekly semaglutide on body weight and safety outcomes in overweight or obese patients were retrieved from PubMed, EMBASE, and Lilacs up to November 2023. Risk of bias was assessed with RoB 2.0, and certainty of evidence (CoE) with GRADE. A random-effects meta-analysis was conducted.

Results Ten publications, with 22.155 patients, were included. Semaglutide decreased relative body weight (MD: −11.80; 95%CI: −13.53 to −10.07; CoE: High), absolute body weight (MD: −11.58; 95%CI: −13.25 to −9.90; CoE: High) and BMI (MD: −4.15; 95%CI: −4.85 to −3.45; CoE: High). Semaglutide also increased the proportion of patients who achieved 5%, 10%, and 15% of weight loss ([weight loss≥5%: RR 2.29, 95% CI: 1.88 to 2.80; CoE: High]; [weight loss≥10%: RR 4.54, 95% CI: 3.45 to 5.98; CoE: High]; [weight loss≥15%: RR 8.29, 95%CI: 5.54 to 12.39; CoE: High]). Semaglutide leads to small risk to adverse events (RR: 1.03; 95%CI: 1 to 1.06; CoE: High), no difference in the serious adverse events (RR: 1.07; 95%CI: 0.70 to 1.62; CoE: Low), but increases in the risk to discontinued treatment (RR: 2.03; 95%CI: 1.87 to 2.20; CoE: High) and gastrointestinal adverse events (RR: 3.26; 95%CI: 1.99 to 5.34; CoE: Moderate).

Conclusion This up-to-date systematic review highlights that once-weekly semaglutide treatment resulted in clinically important weight loss, becoming a promising adjuvant therapy for obesity.

Keywords

GLP-1 receptor agonist - obesity - weight management - anti-obesity drugs - meta-analysis

Publication History

Received: 12 February 2024
Received: 21 March 2024

Accepted: 06 April 2024

Accepted Manuscript online:
10 April 2024

Article published online:
13 June 2024

• References

• 1 Gonzalez-Muniesa P, Martinez-Gonzalez MA, Hu FB. et al. Obesity. Nat Rev Dis Primers 2017; 3: 17034 DOI: 10.1038/nrdp.2017.34.
• 2 Hachula M, Kosowski M, Zielanska K. et al. The Impact of various methods of obesity treatment on the quality of life and mental health-A narrative review. Int J Environ Res Public Health 2023; 20 DOI: 10.3390/ijerph20032122.
• 3 Boutari C, Mantzoros CS. A 2022 update on the epidemiology of obesity and a call to action: As its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 2022; 133: 155217 DOI: 10.1016/j.metabol.2022.155217.
• 4 Kim TN. Barriers to obesity management: Patient and physician factors. J Obes Metab Syndr 2020; 29: 244-247 DOI: 10.7570/jomes20124.
• 5 Muller TD, Bluher M, Tschop MH. et al. Anti-obesity drug discovery: Advances and challenges. Nat Rev Drug Discov 2022; 21: 201-223 DOI: 10.1038/s41573-021-00337-8.
• 6 Wang JY, Wang QW, Yang XY. et al. GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach. Front Endocrinol (Lausanne) 2023; 14: 1085799 DOI: 10.3389/fendo.2023.1085799.
• 7 Singh G, Krauthamer M, Bjalme-Evans M. Wegovy (semaglutide): A new weight loss drug for chronic weight management. J Investig Med 2022; 70: 5-13 DOI: 10.1136/jim-2021-001952.
• 8 Garvey WT, Batterham RL, Bhatta M. et al. Two-year effects of semaglutide in adults with overweight or obesity: The STEP 5 trial. Nat Med 2022; 28: 2083-2091 DOI: 10.1038/s41591-022-02026-4.
• 9 Rubino D, Abrahamsson N, Davies M. et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 Randomized Clinical Trial. JAMA 2021; 325: 1414-1425 DOI: 10.1001/jama.2021.3224.
• 10 Rubino DM, Greenway FL, Khalid U. et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: The STEP 8 Randomized Clinical Trial. JAMA 2022; 327: 138-150 DOI: 10.1001/jama.2021.23619.
• 11 Wadden TA, Bailey TS, Billings LK. et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 Randomized Clinical Trial. JAMA 2021; 325: 1403-1413 DOI: 10.1001/jama.2021.1831.
• 12 Wilding JPH, Batterham RL, Calanna S. et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989-1002 DOI: 10.1056/NEJMoa2032183.
• 13 Davies M, Faerch L, Jeppesen OK. et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021; 397: 971-984 DOI: 10.1016/S0140-6736(21)00213-0.
• 14 Kadowaki T, Isendahl J, Khalid U. et al. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): A randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol 2022; 10: 193-206 DOI: 10.1016/S2213-8587(22)00008-0.
• 15 Gao X, Hua X, Wang X. et al. Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 2022; 13: 935823 DOI: 10.3389/fphar.2022.935823.
• 16 He K, Guo Q, Zhang H. et al. Once-weekly semaglutide for obesity or overweight: A systematic review and meta-analysis. Diabetes Obes Metab 2022; 24: 722-726 DOI: 10.1111/dom.14612.
• 17 Zhong P, Zeng H, Huang M. et al. Efficacy and safety of once-weekly semaglutide in adults with overweight or obesity: A meta-analysis. Endocrine 2022; 75: 718-724 DOI: 10.1007/s12020-021-02945-1.
• 18 Higgins JPTTJ, Chandler J, Cumpston M. et al. Cochrane Handbook for Systematic Reviews of Interventions: Cochrane. 2023
• 19 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6: e1000097 DOI: 10.1371/journal.pmed.1000097.
• 20 Jensen MD, Ryan DH, Apovian CM. et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129: S102-138 DOI: 10.1161/01.cir.0000437739.71477.ee.
• 21 Sterne JAC, Savovic J, Page MJ. et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898 DOI: 10.1136/bmj.l4898.
• 22 Balshem H, Helfand M, Schunemann HJ. et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401-406 DOI: 10.1016/j.jclinepi.2010.07.015.
• 23 Sterne JA, Sutton AJ, Ioannidis JP. et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002 DOI: 10.1136/bmj.d4002.
• 24 Blundell J, Finlayson G, Axelsen M. et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab 2017; 19: 1242-1251 DOI: 10.1111/dom.12932.
• 25 Friedrichsen M, Breitschaft A, Tadayon S. et al. The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes Obes Metab 2021; 23: 754-762 DOI: 10.1111/dom.14280.
• 26 Jensterle M, Ferjan S, Vovk A. et al. Semaglutide reduces fat accumulation in the tongue: A randomized single-blind, pilot study. Diabetes Res Clin Pract 2021; 178: 108935 DOI: 10.1016/j.diabres.2021.108935.
• 27 Kosiborod MN, Abildstrom SZ, Borlaug BA. et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 2023; 389: 1069-1084 DOI: 10.1056/NEJMoa2306963.
• 28 Lincoff AM, Brown-Frandsen K, Colhoun HM. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023; 389: 2221-2232 DOI: 10.1056/NEJMoa2307563.
• 29 Qin W, Yang J, Deng C. et al Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial. Diabetes Obes Metab 2023; 26: 911-923 DOI: 10.1111/dom.15386. 10.1111/dom.15386
• 30 Jensterle M, Rizzo M, Haluzik M. et al. Efficacy of GLP-1 RA approved for weight management in patients with or without diabetes: A narrative review. Adv Ther 2022; 39: 2452-2467 DOI: 10.1007/s12325-022-02153-x.
• 31 Administration. FaD. Wegovy Prescribing Information. In; 2021
• 32 Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab 2018; 27: 740-756 DOI: 10.1016/j.cmet.2018.03.001.
• 33 Gabery S, Salinas CG, Paulsen SJ. et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 2020; 5 DOI: 10.1172/jci.insight.133429.
• 34 Hall S, Isaacs D, Clements JN. Pharmacokinetics and clinical implications of semaglutide: A new glucagon-like peptide (GLP)-1 receptor agonist. Clin Pharmacokinet 2018; 57: 1529-1538 DOI: 10.1007/s40262-018-0668-z.
• 35 Khera R, Murad MH, Chandar AK. et al. Association of pharmacological treatments for obesity with weight loss and adverse events: A systematic review and meta-analysis. JAMA 2016; 315: 2424-2434 DOI: 10.1001/jama.2016.7602.
• 36 Konwar M, Bose D, Jaiswal SK. et al. Efficacy and safety of liraglutide 3.0 mg in patients with overweight and obese with or without diabetes: A systematic review and meta-analysis. Int J Clin Pract 2022; 2022: 1201977 DOI: 10.1155/2022/1201977.
• 37 Lean ME, Leslie WS, Barnes AC. et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. Lancet 2018; 391: 541-551 DOI: 10.1016/S0140-6736(17)33102-1.
• 38 Heerspink HJL, Apperloo E, Davies M. et al. Effects of semaglutide on albuminuria and kidney function in people with overweight or obesity with or without type 2 diabetes: Exploratory analysis from the STEP 1, 2, and 3 trials. Diabetes Care 2023; 46: 801-810 DOI: 10.2337/dc22-1889.
• 39 Rossing P, Baeres FMM, Bakris G. et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 2023; 38: 2041-2051 DOI: 10.1093/ndt/gfad009.
• 40 Ghusn W, Fansa S, Anazco D. et al Weight loss and cardiovascular disease risk outcomes of semaglutide: A one-year multicentered study. Int J Obes (Lond) 2024; FebL 1 DOI: 10.1038/s41366-023-01456-5. 10.1038/s41366-023-01456-5
• 41 Bendotti G, Montefusco L, Lunati ME. et al. The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharmacol Res 2022; 182: 106320 DOI: 10.1016/j.phrs.2022.106320.
• 42 Iacobellis G, Villasante Fricke AC. Effects of semaglutide versus dulaglutide on epicardial fat thickness in subjects with type 2 diabetes and obesity. J Endocr Soc 2020; 4: bvz042 DOI: 10.1210/jendso/bvz042.
• 43 Ji L, Dong X, Li Y. et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes in SUSTAIN China: A 30-week, double-blind, phase 3a, randomized trial. Diabetes Obes Metab 2021; 23: 404-414 DOI: 10.1111/dom.14232.
• 44 Shu Y, He X, Wu P. et al. Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system. Front Public Health 2022; 10: 996179 DOI: 10.3389/fpubh.2022.996179.
• 45 Wharton S, Calanna S, Davies M. et al. Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes Metab 2022; 24: 94-105 DOI: 10.1111/dom.14551.
• 46 Bergmann NC, Davies MJ, Lingvay I. et al. Semaglutide for the treatment of overweight and obesity: A review. Diabetes Obes Metab 2023; 25: 18-35 DOI: 10.1111/dom.14863.
• 47 Nagendra L, Bg H, Sharma M. et al. Semaglutide and cancer: A systematic review and meta-analysis. Diabetes Metab Syndr 2023; 17: 102834 DOI: 10.1016/j.dsx.2023.102834.
• 48 European Medicines Agency. Guideline on clinical evaluation of medicinal products used in weight management. 2016 https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-evaluation-medicinal-products-used-weight-management-revision-1_en.pdf