Background <p>Individuals with schizophrenia suffer from reduced life expectancy, primarily due to obesity-related metabolic disorders and cardiovascular disease (CVD). The presence of cardiac autonomic neuropathy (CAN) may contribute to CVD, but CAN is reversible, and it may improve following weight loss. Semaglutide, a GLP-1 receptor agonist (GLP-1RA), induces weight loss and improves cardio-metabolic risk factors. Therefore, this study evaluated the impact of semaglutide on CAN in individuals with schizophrenia.</p> Methods <p>We conducted a double-blind, randomized, placebo-controlled trial with 154 adults (18–60 years, BMI ≥27 kg/m²) who were receiving treatment with second-generation antipsychotics (SGAs) for schizophrenia and prediabetes (HbA1c: 39–47 mmol/mol). Participants were randomized (1:1) to receive once-weekly semaglutide or placebo (titrated to 1.0 mg or maximally tolerated dose) for 30 weeks.</p> Results <p>A total of 141 participants completed the trial (semaglutide: 74; placebo: 67). CAN prevalence was high (84%), with 50% of the participants showing definite CAN. CAN prevalence increased with obesity: the risk of having definite CAN increased significantly from BMI 30–35 kg/m² and to BMI &gt; 35 kg/m² (<i>p</i> &lt; 0.001). Clozapine treatment was associated with CAN (<i>p</i> &lt; 0.001). Semaglutide treatment for 30 weeks reduced BMI by 2.86 kg/m² but did not alter CAN levels (<i>p</i> = 0.516). No significant changes were observed in the placebo group.</p> Interpretation <p>CAN is highly prevalent in patients with schizophrenia, and CAN correlates with BMI and clozapine treatment. Although semaglutide reduced BMI, CAN remained unchanged, despite its relationship with BMI. Thus, longer periods with semaglutide treatment may be required before CAN improves.</p> Trial registration <p>Clinicaltrials.gov identifier: NCT05193578.</p>