Glucagon-Like Peptide-1 Receptor Agonists in Individuals With Severe Mental Illness: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

ObjectiveThis systematic review and meta-analysis evaluated the efficacy, acceptability, and tolerability of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in individuals with severe mental illness (SMI).MethodsPubMed, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were searched on December 1, 2025, for randomized controlled trials (RCTs) of GLP-1RAs in participants with SMI. Primary outcomes were weight reduction, glycated hemoglobin (HbA1c) reduction, all-cause dropouts, and adverse-effect dropouts. Mean differences (MDs) and risk ratios (RRs) were estimated using a frequentist random-effects model.ResultsIncluded were 10 RCTs (N = 665) of exenatide, liraglutide, and semaglutide. Participants were those with schizophrenia, schizophrenia-spectrum disorders, or bipolar disorder with cardiometabolic risk. Compared with placebo/usual care, GLP-1RAs significantly reduced weight (MD = -6.17 kg, 95% CI: -9.10 to -3.25,= 91.8%, 9 trials) and HbA1c (MD = -0.31%, 95% CI: -0.40 to -0.22,= 51.3%, 8 trials). All-cause dropouts did not differ significantly between groups (RR = 0.98, 95% CI: 0.71 to 1.35,= 28.5%, 10 trials), nor did adverse-effect dropouts (RR = 0.99, 95% CI: 0.35 to 2.77,= 31.6%, 5 trials). Low-certainty evidence supports the tolerability and efficacy of GLP-1RAs for weight and HbA1c reduction. Moderate-certainty evidence also supports their acceptability.ConclusionLimited evidence suggests that GLP-1RAs may reduce body weight and slightly reduce HbA1c in individuals with SMI who have prediabetes or are overweight/obese. GLP-1RAs are likely acceptable and may be tolerated in this population.