Metformin and GLP-1 receptor agonists for antipsychotic-induced metabolic disturbances: a systematic review and network meta-analysis

The management of antipsychotic-induced metabolic disturbances (AIMD) represents a significant challenge in psychiatric clinical practice. This study aimed to synthesize randomized evidence and estimate the relative effects of metformin and GLP-1 receptor agonists (GLP-1 RAs) on multidimensional metabolic indicators and psychiatric symptoms in patients with AIMD using a network meta-analysis framework. Randomized controlled trials (RCTs) published up to December 5, 2025, were identified from PubMed, Embase, Cochrane Library, and Web of Science. Eligible studies evaluated metformin or GLP-1 RAs for at least 12 weeks during ongoing antipsychotic treatment. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Random-effects frequentist network meta-analysis was performed in Stata 17.0 MP. Intervention rankings were determined by calculating the surface under the cumulative ranking curve (SUCRA). Univariate network meta-regression was applied to explore the impact of study-level covariates on treatment efficacy. Evidence quality was rated based on the CINeMA framework. Twenty-nine Studies involving 1,721 patients were included. Median study-level age was 36.2 years, 47.7% of participants were male, and median treatment duration was 16 weeks. Compared with control groups, semaglutide was associated with reductions in body mass index (BMI) (MD = -3.55, 95% CI: -4.27 to -2.84), waist circumference (WC) (MD = -6.34, 95% CI: -8.17 to -4.51), glycated hemoglobin A1c (HbA1c) (MD = -0.44, 95% CI: -0.53 to -0.35), and fasting blood glucose (FBG) (MD = -0.53, 95% CI: -0.88 to -0.18). Metformin was associated with reductions in lipid metabolism markers, including total cholesterol (TC) and triglycerides (TG), and showed an exploratory potential benefit for psychiatric symptom scores (SMD = -0.31, 95% CI: -0.55 to -0.06). Indirect network estimates suggest that these interventions may have different outcome profiles, with GLP-1 RAs showing potential benefits for weight-related and glycemic outcomes and metformin showing potential benefits for lipid parameters and psychiatric symptom scores. However, because active-treatment comparisons were indirect and the transitivity assumption remains uncertain, these findings should be interpreted as exploratory evidence that may inform clinical discussion and future research.