Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists and Co-agonists for Weight Loss Among Adults Without Diabetes : An Updated Systematic Review.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management.

PURPOSE: To update our prior systematic review evaluating the efficacy and safety of GLP-1 RAs and co-agonists among adults with overweight or obesity without diabetes.

DATA SOURCES: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from 5 October 2024 through 25 March 2026.

STUDY SELECTION: Randomized controlled trials ([RCTs] treatment duration ≥16 weeks).

DATA EXTRACTION: Two reviewers independently extracted data.

DATA SYNTHESIS: Thirty-eight RCTs (n = 25 816) were included, adding 14 new trials (n = 11 000) to the prior review. Among commercially available therapies, placebo-subtracted weight loss reached up to -5.8% (95% CI, -8.0% to -3.6%) for liraglutide, -14.8% (CI, -16.2% to -13.4%) for subcutaneous semaglutide, -14.3% (CI, -17.2% to -11.4%) for oral semaglutide, -12.4% (CI, -15.1% to -9.7%) for orforglipron, and -19.0% (CI, -21.6% to -16.4%) for tirzepatide. Numerically greater placebo-subtracted reductions were seen with emerging multiagonists, including -23.9% (CI, -29.3% to -18.5%) with amycretin and -22.1% (CI, -24.9% to -19.3%) with retatrutide. Gastrointestinal adverse events (AEs) remained common (GLP-1 RA vs. placebo: 76.0% vs. 40.1%). Discontinuation due to AEs was generally low (10.7% vs. 3.4%) but numerically higher with some oral agents. Serious AEs (6.5% vs. 5.2%) and deaths (0.1% vs. 0.0%) were rare, with no new safety signals identified. Head-to-head data showed greater weight loss with semaglutide and JNJ-64565111 than liraglutide and greater weight loss with tirzepatide and cagrilintide-semaglutide (CagriSema; Novo Nordisk) than semaglutide.

LIMITATIONS: Heterogeneity precluded quantitative synthesis. Safety outcomes were inconsistently reported.

CONCLUSION: Glucagon-like peptide-1 receptor agonists demonstrate substantial weight loss in adults without diabetes, with an expanding range of therapeutic options, including oral and multiagonist therapies.

PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42024505558).