{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T11:34:54Z","timestamp":1792928094977,"version":"4.5.0"},"reference-count":30,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"\n Importance<\/jats:title>\n Patients with schizophrenia have reduced life expectancy due to cardiovascular disease and obesity-related type 2 diabetes, exacerbated by second-generation antipsychotic (SGA) medication. Existing interventions have shown limited effect.<\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n \n To assess the effect of the once-weekly glucagon-like peptide-1 receptor agonist semaglutide in SGA-treated adults (aged 18-60 years) with schizophrenia, prediabetes (glycosylated hemoglobin A\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n [HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n ], 5.7%-6.4% of total hemoglobin) (to convert HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n from percentage of total hemoglobin to mmol\/mol, use the following formula: (HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n %\u2009\u2212\u20092.152)\/0.09148), and overweight or obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, \u226527).\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This placebo-controlled, double-blinded randomized clinical trial was conducted from January 2022 to May 2024, with 30 weeks of follow-up, among regional community-based mental health services in 2 regions of Denmark (Region of Southern Denmark and Region of Zealand). SGA-treated patients with schizophrenia, prediabetes, and overweight or obesity were randomized to semaglutide or placebo. Data analysis was completed from May 2024 to January 2025.<\/jats:p>\n <\/jats:sec>\n \n Intervention<\/jats:title>\n Once-weekly subcutaneous semaglutide or placebo for 30 weeks; semaglutide was titrated up to 1.0 mg\/week over 8 weeks.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary outcome was change in HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n . Secondary end points included changes in body weight, schizophrenia symptoms based on Positive and Negative Syndrome Scale 6 (PANSS-6) score, and physical and mental quality of life (QoL) (assessed via the 36-item Short Form Survey, version 2 [SF-36v2]).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 154 patients were recruited and randomized 1:1 to semaglutide or placebo (87 female participants (56.5%); mean [SD] age, 38.3 [10.7] years). Of 154 randomized patients, 141 (91.5%) completed the trial\u201474 of 77 patients randomized to semaglutide (96%) and 67 of 77 randomized to placebo (87%). Semaglutide reduced HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n by 0.46% of total hemoglobin (95% CI, \u22120.56% to \u22120.36%) and body weight by 9.21 kg (95% CI, \u221211.68 to \u22126.75). An HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n less than 5.7% of total hemoglobin was achieved in 81% vs 19% of patients treated with semaglutide and placebo, respectively (\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001); improvements in high-density cholesterol by 10.81 mg\/dL (95% CI, 2.70-18.53;\n P<\/jats:italic>\n \u2009=\u2009.007) and triglycerides by \u221229.20 mg\/dL (95% CI, \u221255.75 to 2.65;\n P<\/jats:italic>\n \u2009=\u2009.03) (to convert to millimoles per liter, multiply by 0.0113) were also observed. Finally, semaglutide improved physical QoL by 3.75 points on the SF-36v2 (95% CI, 1.52-5.98;\n P<\/jats:italic>\n \u2009=\u2009.001) but had no significant effect on mental QoL scores or PANSS-6 score. Gastrointestinal symptoms were more frequent in semaglutide-treated patients. A few semaglutide-treated patients were hospitalized more frequently than observed in the placebo-treated group, but the number of serious adverse effects did not differ between groups.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this multicenter, double-blinded randomized clinical trial, 30 weeks of administration of semaglutide, up to 1.0 mg\/week, was safe, lowered blood glucose (as measured by HbA\n \n 1\n c<\/jats:sc>\n <\/jats:sub>\n ) and weight, and improved physical QoL in SGA-treated patients with schizophrenia, prediabetes, and obesity without worsening mental health.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT05193578<\/jats:ext-link>\n <\/jats:p>\n 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