Adjunctive GLP-1 receptor agonists for cardiometabolic risk in antipsychotic-treated patients: A GRADE-assessed meta-analysis of randomized trials.

BACKGROUND

Patients with schizophrenia spectrum or bipolar disorders have reduced life expectancy due to cardiometabolic risk. We conducted this meta-analysis to evaluate glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for their effects on cardiometabolic outcomes.

METHODS

We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane up to May 2026 for randomized controlled trials (RCTs). We pooled continuous outcomes as mean differences (MDs) and dichotomous outcomes as risk ratios (RRs) using random-effects models with 95% confidence intervals (CIs).

RESULTS

We included 8 RCTs with 664 patients. Compared with control, GLP-1 RA significantly reduced body weight (MD: -6.74, 95% CI: -10.05 to -3.43), body mass index (BMI; MD: -2.37 kg/m2, 95% CI: -3.52 to -1.23), waist circumference (MD: -4.27 cm, 95% CI: -6.65 to -1.89), HbA1c (MD: -0.61%, 95% CI: -1.06 to -0.17), and fasting glucose (MD: -6.82, 95% CI: -11.89 to -1.76). Subgroup analyses by GLP-1 RA type showed that semaglutide produced the greatest reductions in body weight (MD: -11.06 kg) and BMI (MD: -3.60 kg/m2), with significant between-subgroup differences (p < 0.05). Adverse events (AEs; p = 0.77), serious AEs (p = 0.09), and discontinuation due to AEs (p = 0.20) were similar between groups. However, GLP-1 RA was associated with a significantly higher risk of gastrointestinal (GI) AEs, including nausea, vomiting, and constipation (all p < 0.01).

CONCLUSION

GLP-1RA, particularly semaglutide, was associated with clinically meaningful improvements in antipsychotic-related cardiometabolic outcomes without compromising psychiatric stability or treatment adherence. However, the significant increase in GI AEs necessitates careful clinical titration. Larger RCTs with longer follow-up are needed to confirm these findings.