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. 2025 Sep 3:e252332.
doi: 10.1001/jamapsychiatry.2025.2332. Online ahead of print.

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

Ashok A Ganeshalingam  1   2   3 , Nicolai Uhrenholt  2   4   5   6 , Sidse Arnfred  6   7 , Peter Gæde  8   9 , Signe Düring  6   7 , Elsebeth N Stenager  10 , Nick Bünger  11 , Andreas K Pedersen  12 , Niels Bilenberg  2   5 , Jan Frystyk  1   2   3
Affiliations

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

Ashok A Ganeshalingam et al. JAMA Psychiatry. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ganeshalingam reported 1-year Phd salary from the Steno Diabetes Center Odense; provision of investigational medicinal product from Novo Nordisk A/S; funding for traveling to the European Association for the Study of Diabetes (EASD) conference 2024 with Novo Nordisk; and grants from Aase and Ejnar Danielsens fond 2024. Dr Uhrenholt reported provision of investigational medicinal product from Novo Nordisk A/S; grant funding for the study administered by hospitals from the Novo Nordisk Foundation; 1-year salary from the Steno Diabetes Center Sjaelland 2021; and salary for nurses from Slagelse Research Grants 2020, 2022, and 2024 (a fund managed by Næstved, Slagelse, and Ringsted Hospitals and The Psychiatry Department of Region Zealand) and from the Region Zealand Health Research Foundation 2022 during the conduct of the study. Dr Arnfred reported grants from the Novo Nordisk Foundation, the Region Zealand Health Research Foundation, Slagelse Research Grants, and the Steno Diabetes Center Sjaelland during the conduct of the study and grants from the Danish Independent Research Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, Region Zealand Health Research Foundation, and Slagelse Research Grants outside the submitted work. Dr Gæde reported lecture fees payable to his institution from AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk and participating in advisory boards for AstraZeneca, Bayer, and Novo Nordisk, with fees made to his institution, outside the submitted work. Dr Düring reported personal fees from Camurus for a lecture not product related but teaching clinicians of integrated dual diagnosis treatment outside the submitted work. Dr Bilenberg reported grants from the Novo Nordisk Foundation during the conduct of the study; grants to another study (an autism parent intervention) from the Lundbeck Foundation, the Novo Nordisk Foundation, and the Tryg Foundation; and personal fees from Novo Nordisk and Takeda for lecturing on seminars outside the submitted work. Dr Frystyk reported grants (running expenses and salary to PhD students, study nurses, and helpers) from the Novo Nordisk Foundation; grants (PhD salary) from the Steno Diabetes Center Odense; provision of active drug and placebo by Novo Nordisk A/S during the conduct of the study; receiving payment from Novo Nordisk A/S for the measurement of insulin-like growth factor 1 in children; speaker fees at 2025 meetings from Eli Lilly A/S and Novo Nordisk outside the submitted work; and having biomarker findings that may be submitted for a patent. No other disclosures were reported.

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