Efficacy and safety of GLP-1 receptor agonists for antipsychotic-related overweight and metabolic dysregulation: a systematic review and meta-analysis.

BACKGROUND

Antipsychotic-related overweight and metabolic dysregulation are highly prevalent among patients with severe mental illness. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial metabolic benefits in the general population, their efficacy and safety in antipsychotic-treated patients remain unclear. This review aimed to systematically evaluate the efficacy and safety of GLP-1RAs in patients with antipsychotic-related overweight and metabolic dysregulation.

METHODS

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1RAs in adults receiving antipsychotic treatment. PubMed, Web of Science, Embase, MEDLINE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to September 13, 2026. Primary outcomes included changes in body weight, body mass index (BMI), HbA1c, and total cholesterol. Random-effects models were used to pool mean differences (MDs) and risk ratios (RRs). This study was registered with PROSPERO (CRD420261290294).

RESULTS

Eight RCTs involving 535 randomized participants were included. GLP-1RAs treatment was associated with significant reductions in body weight (MD = -6.54 kg, 95% CI: -9.80 to -3.29, P < 0.001, I2 = 92%), BMI (MD = -2.34 kg/m2, 95% CI: -3.34 to -1.34, P < 0.001, I² = 85%), HbA1c (MD = -0.32%, 95% CI: -0.39 to -0.26, P < 0.001, I² = 52%), waist circumference (MD = -5.22 cm, 95% CI: -6.55 to -3.88, P < 0.001, I2 = 27%), visceral fat mass (MD = -0.31 kg, 95% CI: -0.46 to -0.16, P < 0.001, I2 = 11%), and LDL-C (MD = -0.16 mmol/L, 95% CI: -0.31 to -0.01, P = 0.03, I2 = 54%), whereas no significant effects were observed for total cholesterol, triglycerides, or HDL-C. Weight reduction was greatest with semaglutide, followed by liraglutide, and increased with longer treatment duration (both P for subgroup differences < 0.05). GLP-1RAs were associated with higher risks of nausea (RR = 1.61, 95% CI: 1.20 to 2.16), vomiting (RR = 2.10, 95% CI: 1.32 to 3.35), and constipation (RR = 2.34, 95% CI: 1.23 to 4.47), but not of diarrhea, serious adverse events (RR = 0.72, 95% CI: 0.49 to 1.06), all-cause discontinuation (RR = 1.05, 95% CI: 0.60 to 1.85), or discontinuation due to adverse events (RR = 2.14, 95% CI: 0.72 to 6.33). Psychiatric adverse events were infrequent and could not be pooled.

CONCLUSION

GLP-1RAs significantly improve weight-related and glycemic outcomes in antipsychotic-treated patients, at the cost of an increased risk of gastrointestinal adverse events. Their psychiatric safety could not be established owing to sparse data. Longer-term trials with standardized safety reporting are warranted.