Highlight
- Semaglutide significantly lowered HbA1c by 0.46% and body weight by over 9 kg in patients with schizophrenia, prediabetes, and obesity on second-generation antipsychotics.
- 81% of semaglutide-treated patients achieved normoglycemia (HbA1c <5.7%) compared to 19% on placebo.
- Improvement in physical quality of life was observed without worsening of psychiatric symptoms or mental quality of life scores.
- Gastrointestinal side effects were more frequent but serious adverse effects were similar between groups.
Study Background
Patients with schizophrenia suffer from substantially reduced life expectancy primarily due to cardiovascular disease and metabolic complications such as type 2 diabetes and obesity. Second-generation antipsychotic (SGA) medications, while effective for psychosis, often exacerbate weight gain and perturb glucose metabolism, compounding these risks. Current lifestyle and pharmacologic interventions for metabolic dysfunction in this population have yielded limited success, necessitating newer, targeted strategies to mitigate these adverse effects and improve long-term outcomes.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, have emerged with robust evidence for glucose lowering, weight reduction, and cardiovascular benefits in type 2 diabetes and obesity. However, their efficacy and safety in the vulnerable schizophrenia population, especially those with prediabetes and obesity, remained inadequately studied prior to the HISTORI trial.
Study Design
HISTORI was a multicenter, placebo-controlled, double-blind randomized clinical trial conducted between January 2022 and May 2024 in two Danish regions (Region of Southern Denmark and Region of Zealand). It enrolled 154 adults aged 18 to 60 years with schizophrenia, prediabetes (defined by HbA1c 5.7%-6.4%), and overweight or obesity (BMI ≥27 kg/m2), all treated with SGAs.
Participants were randomized 1:1 to receive once-weekly subcutaneous semaglutide, titrated to 1.0 mg/week over 8 weeks, or matching placebo for 30 weeks. Primary endpoint was change in HbA1c. Secondary endpoints included changes in body weight, schizophrenia symptoms measured by the Positive and Negative Syndrome Scale 6-item version (PANSS-6), and physical and mental quality of life assessed via the SF-36v2 questionnaire.
Key Findings
Of 154 randomized patients (mean age 38.3 years; 56.5% female), 141 (91.5%) completed the study. Semaglutide treatment resulted in a statistically and clinically significant reduction in HbA1c by 0.46% of total hemoglobin (95% CI, -0.56% to -0.36%) compared to placebo, translating into a meaningful improvement in glycemic status.
Body weight decreased by a marked 9.21 kg (95% CI, -11.68 to -6.75), substantially exceeding placebo effects. Favorable changes in lipid profiles were also observed, with significant increases in high-density lipoprotein cholesterol (+10.81 mg/dL; P = .007) and reductions in triglycerides (-29.20 mg/dL; P = .03), favorable for cardiovascular risk mitigation.
Crucially, the proportion of patients achieving normoglycemia (HbA1c <5.7%) was 81% with semaglutide versus only 19% with placebo (P < .001), indicating reversal of prediabetes in the majority of treated patients.
Physical quality of life improved significantly (+3.75 points SF-36v2; P = .001). Importantly, semaglutide did not worsen psychiatric symptoms as assessed by PANSS-6 scores, nor did it impact mental quality of life measures, addressing concerns about potential neuropsychiatric side effects.
Adverse events were mostly limited to more frequent gastrointestinal symptoms in the semaglutide group, consistent with the drug's known safety profile. While some semaglutide-treated patients had more hospitalizations, the incidence of serious adverse events did not differ significantly between groups.
Expert Commentary
The HISTORI trial offers robust, randomized evidence supporting semaglutide as a safe and effective metabolic intervention in a high-risk, antipsychotic-treated schizophrenia population with prediabetes and obesity. The substantial reductions in HbA1c and weight, coupled with improvements in lipid profiles and physical quality of life, highlight the drug’s potential to address the metabolic comorbidities contributing to the excess cardiovascular burden in schizophrenia.
The lack of psychiatric symptom exacerbation is particularly reassuring given prior concerns about GLP-1 RA effects on mental health. This trial’s design and comprehensive follow-up offer strong internal validity, though external generalizability outside the Danish population should be cautiously interpreted.
Potential limitations include the relatively short duration (30 weeks) which may not capture long-term adherence, cardiovascular outcomes, or safety signals fully. Moreover, the trial excluded patients with type 2 diabetes, thus the applicability to those with established diabetes remains to be established. Nevertheless, the biological plausibility of semaglutide’s metabolic benefits is supported by its known mechanisms enhancing insulin secretion, suppressing glucagon, and promoting satiety leading to weight loss.
Conclusion
The HISTORI randomized trial supports the use of once-weekly semaglutide in adult patients with schizophrenia who are treated with second-generation antipsychotics and suffer from prediabetes and overweight or obesity. Semaglutide significantly improved glycemic control, induced marked weight loss, and enhanced physical quality of life without worsening schizophrenia symptoms or mental quality of life. These findings pave the way for integrating GLP-1 receptor agonists into the management of metabolic comorbidities in psychiatric populations, a vital step in reducing excess morbidity and mortality.
Future studies should evaluate long-term cardiovascular outcomes, cost-effectiveness, and mechanistic pathways to refine treatment algorithms for this vulnerable group.
Funding and Trial Registration
This study was conducted with funding and support as per the original investigators. The trial is registered at ClinicalTrials.gov under identifier NCT05193578.
References
Ganeshalingam AA, Uhrenholt N, Arnfred S, Gæde P, Düring S, Stenager EN, Bünger N, Pedersen AK, Bilenberg N, Frystyk J. Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial. JAMA Psychiatry. 2025 Sep 3:e252332. doi: 10.1001/jamapsychiatry.2025.2332. Epub ahead of print. PMID: 40900607; PMCID: PMC12409653.
