• Areesha Moiz, Kristian B Filion, Helia Toutounchi, Michael A Tsoukas, YuOriana H YOHY0000-0003-4877-557XCentre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division, Tricia M Peters, and Mark J Eisenberg.
• Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada (A.M.).
• Ann. Intern. Med. 2025 Jan 7.

BackgroundRecent 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.PurposeTo assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes.Data SourcesMEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024.Study SelectionPlacebo-controlled RCTs in otherwise healthy participants with overweight or obesity.Data ExtractionThe 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 SynthesisA total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare.LimitationsNo head-to-head RCTs were available. Heterogeneity prevented meta-analysis.ConclusionGLP-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 SourceNone. (PROSPERO: CRD42024505558).

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