Semaglutide may Improve Insulin Sensitivity in Schizophrenia Patients with Prediabetes: Study suggests
Denmark: A study published in Diabetes Care has revealed that semaglutide improves insulin sensitivity in patients with schizophrenia who have prediabetes and are overweight or obese. The drug significantly reduced fasting glucose levels and insulin resistance, primarily due to weight loss.
The findings come from the HISTORI trial, a 30-week randomized, double-blind, placebo-controlled study that evaluated the metabolic effects of weekly semaglutide therapy in individuals with schizophrenia receiving second-generation antipsychotic medications. These drugs are widely used in the management of Schizophrenia but are often associated with weight gain and metabolic complications such as Prediabetes and Obesity.
The trial was led by Ashok A. Ganeshalingam and colleagues from the Endocrine Research Unit at Odense University Hospital. The researchers aimed to investigate how semaglutide influences insulin sensitivity, insulin resistance, and pancreatic β-cell function, and whether any metabolic benefits are linked to weight reduction.
A total of 154 participants with schizophrenia, prediabetes, and overweight or obesity who were receiving second-generation antipsychotics were enrolled in the trial. They were randomly assigned to receive either semaglutide 1.0 mg once weekly or placebo for 30 weeks. Of these, 141 participants, representing more than 91% of the cohort, completed the study. The study population had a mean age of 38.3 years and included 56% women.
Researchers assessed multiple metabolic markers at baseline and at the end of the study period. These included fasting glucose, insulin, C-peptide levels, indices of insulin sensitivity and insulin resistance, β-cell function, and body weight. Complete insulin-related data were available for 131 participants.
The trial revealed the following findings:
- Participants receiving semaglutide showed significantly greater improvements in metabolic parameters compared with those receiving a placebo.
- Fasting glucose levels decreased by 0.87 mmol/L in the semaglutide group.
- Insulin sensitivity improved significantly among participants treated with semaglutide.
- Insulin resistance was significantly reduced in the semaglutide group.
- Participants treated with semaglutide experienced a mean weight loss of 9.2 kg during the study period.
- The reduction in body weight significantly mediated the improvements observed in both insulin sensitivity and insulin resistance.
- Fasting insulin levels showed a decline in the semaglutide group, but the reduction did not reach statistical significance.
- C-peptide levels also decreased among participants receiving semaglutide, although the change was not statistically significant.
- A modest increase in pancreatic β-cell function was observed in the semaglutide group, but this change was not statistically significant.
Overall, the findings indicate that semaglutide therapy can meaningfully improve metabolic health in individuals with schizophrenia who develop metabolic disturbances while receiving antipsychotic medications. The investigators concluded that semaglutide significantly enhanced insulin sensitivity, reduced insulin resistance, lowered fasting glucose, and produced notable weight loss in this high-risk population. However, the treatment had minimal direct impact on β-cell function.
The authors suggest that semaglutide may represent a promising therapeutic approach for addressing metabolic dysfunction associated with antipsychotic treatment in patients with schizophrenia.
Reference:
Ashok A. Ganeshalingam, Nicolai Uhrenholt, Sidse Arnfred, Peter Gæde, Andreas K. Pedersen, Niels Bilenberg, Jan Frystyk; Semaglutide Effects on Insulin Sensitivity and β-Cell Function in Patients With Schizophrenia, Prediabetes, and Obesity Treated With Second-Generation Antipsychotics: Findings From the HISTORI Trial, a 30-Week Randomized, Placebo-Controlled Trial With Semaglutide 1.0 mg Weekly. Diabetes Care 2026; dc252041. https://doi.org/10.2337/dc25-2041
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