Semaglutide and Other GLP-1 Agonists for Antipsychotic-Associated Metabolic Dysfunction in Schizophrenia

BACKGROUND: Individuals with schizophrenia spectrum disorders experience a high burden of metabolic abnormalities, which are further exacerbated by antipsychotic treatment and contribute to increased cardiovascular morbidity and premature mortality. Glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated metabolic benefits in the general population; however, their effectiveness and safety in individuals with schizophrenia remain uncertain. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials evaluating the effects of semaglutide and other GLP-1 receptor agonists on metabolic outcomes in adults with schizophrenia spectrum disorders receiving antipsychotic treatment. The review was conducted in accordance with PRISMA 2020 guidelines, with the protocol prospectively registered in PROSPERO (CRD420251248437). Electronic databases were searched from inception to the final search date. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and certainty of evidence was evaluated using the GRADE approach. Random-effects meta-analyses were performed. RESULTS: Seven randomized controlled trials involving 446 participants were included. GLP-1 receptor agonist therapy was associated with a statistically significant reduction in body weight compared with control (-6.10 [95% CI: -12.10 to -0.10], P=0.05) although heterogeneity was substantial (I²=99%). Significant reductions were also observed in body mass index, waist circumference, and fasting plasma glucose. Effects on lipid parameters, insulin-related outcomes, and blood pressure were inconsistent and generally not statistically significant. Serious adverse events were less frequent in the intervention group. The certainty of evidence ranged from low to moderate, primarily due to heterogeneity and imprecision. CONCLUSIONS: GLP-1 receptor agonists are associated with statistically significant improvements in body weight and selected glycemic parameters among adults with schizophrenia spectrum disorders treated with antipsychotics. However, substantial heterogeneity, shorter study population, and low certainty of evidence restrict the strength of these conclusions. Larger, well-designed randomized controlled trials with longer follow-up and standardized outcome reporting are needed to better define the efficacy and safety of GLP-1 receptor agonists in this population.