Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial.

IMPORTANCE: 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. OBJECTIVES: 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 A1c [HbA1c], 5.7%-6.4% of total hemoglobin) (to convert HbA1c from percentage of total hemoglobin to mmol/mol, use the following formula: (HbA1c % - 2.152)/0.09148), and overweight or obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, ≥27). DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION: Once-weekly subcutaneous semaglutide or placebo for 30 weeks; semaglutide was titrated up to 1.0 mg/week over 8 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in HbA1c. 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]). RESULTS: 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-74 of 77 patients randomized to semaglutide (96%) and 67 of 77 randomized to placebo (87%). Semaglutide reduced HbA1c by 0.46% of total hemoglobin (95% CI, -0.56% to -0.36%) and body weight by 9.21 kg (95% CI, -11.68 to -6.75). An HbA1c less than 5.7% of total hemoglobin was achieved in 81% vs 19% of patients treated with semaglutide and placebo, respectively (P < .001); improvements in high-density cholesterol by 10.81 mg/dL (95% CI, 2.70-18.53; P = .007) and triglycerides by -29.20 mg/dL (95% CI, -55.75 to 2.65; P = .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; P = .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. CONCLUSIONS AND RELEVANCE: 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 HbA1c) and weight, and improved physical QoL in SGA-treated patients with schizophrenia, prediabetes, and obesity without worsening mental health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05193578.