BACKGROUND: The rapid development of multi-receptor drugs targeting glucagon-like peptide-1 receptor (GLP-1R) is driving significant advancements in the treatment of individuals with type 2 diabetes and obesity. This systematic review and network meta-analysis aims to compare the efficacy and safety of multi-receptor drugs in adults with overweight or obesity, with or without type 2 diabetes. METHODS: A systematic search was conducted in PubMed, Cochrane, Web of Science, Embase, CNKI, and WanFang databases up to May 12, 2024. Randomized controlled trials (RCTs) with an intervention duration of at least 12 weeks were included. The population of interest consisted of individuals with overweight or obesity, with or without type 2 diabetes. Eligible studies compared multi-receptor drugs with placebo or other multi-receptor drugs. The primary outcomes were weight reduction, glycated hemoglobin (HbA RESULTS: A total of 24 trials, involving 9165 participants, were included. Retatrutide (mean difference (MD): -11.91 kg, 95% CI: -19.00 to -4.82, P-score: 0.80, p: 0.0003) and Tirzepatide (MD: -12.78 kg, 95% CI: -16.10 to -9.46, P-score: 0.89, p <
0.0001) exhibited superior efficacy in reducing body weight, with all other agents except Mazdutide (MD: -5.31 kg, 95% CI: -9.78 to -0.84, P-score: 0.37, p: 0.0189) achieving reductions of over 8 kg. In patients with type 2 diabetes, all agents reduced HbA CONCLUSIONS: Multi-receptor drugs demonstrated substantial therapeutic potential in weight management, glycemic control, and blood pressure regulation in adults with overweight or obesity, with or without diabetes, with a generally favorable safety profile. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42024554005.