BACKGROUND: Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes. PURPOSE: To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes. DATA SOURCES: MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024. STUDY SELECTION: Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity. DATA EXTRACTION: The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs. DATA SYNTHESIS: A total of 26 RCTs comprising 15 491 participants (72% female
mean body mass index, 30 to 41 kg/m LIMITATIONS: No head-to-head RCTs were available. Heterogeneity prevented meta-analysis. CONCLUSION: GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42024505558).