Glucagon-like peptide-1 receptor agonists in individuals with severe mental illness: A systematic review and meta-analysis of randomized controlled trials

Objective This 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). Methods PubMed, Embase, the Cochrane Library, Google Scholar, and Clinical- Trials.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. Results Included 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, I 2 = 91.8%, 9 trials) and HbA1c (MD = 0.31%, 95% CI: 0.40 to 0.22, I 2 = 51.3%, 8 trials). All-cause dropouts did not differ significantly between groups (RR = 0.98, 95% CI: 0.71 to 1.35, I 2 = 28.5%, 10 trials), nor did adverse effect dropouts (RR = 0.99, 95% CI: 0.35 to 2.77, I 2 = 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. Conclusion The available 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 generally acceptable and tolerated in this population.