Background
People living with schizophrenia often need second-generation antipsychotic medicines to control symptoms such as hallucinations, delusions, and disorganized thinking. These medications can be highly effective for mental health, but they are also well known to increase the risk of weight gain, elevated blood sugar, insulin resistance, and eventually type 2 diabetes. For patients who already have prediabetes and obesity, this metabolic burden can become a major long-term health problem.
Semaglutide is a glucagon-like peptide-1 receptor agonist, or GLP-1 receptor agonist, originally developed to treat type 2 diabetes and later widely used for obesity management. It helps lower blood glucose, reduces appetite, and often leads to meaningful weight loss. Because weight gain and metabolic dysfunction are common in people treated with antipsychotics, researchers have been interested in whether semaglutide might also help this high-risk psychiatric population.
The HISTORI trial was designed to examine whether semaglutide could improve insulin sensitivity, reduce insulin resistance, and support β-cell function in overweight or obese adults with schizophrenia and prediabetes who were receiving second-generation antipsychotics.
Study Design
This was a 30-week, double-blind, randomized, placebo-controlled trial. A total of 154 participants were assigned to receive either semaglutide 1.0 mg once weekly or placebo, with 77 participants in each group. Most participants completed the study: 141 individuals, or 91.5%, finished the full trial period.
Participants were adults with schizophrenia, overweight or obesity, and prediabetes. At baseline and at the end of the study, investigators measured fasting glucose, fasting insulin, C-peptide, and body weight. They also calculated standard markers of glucose regulation and insulin action, including HOMA2 for β-cell function, HOMA2 for insulin sensitivity, and HOMA for insulin resistance. These measures are commonly used to estimate how well the pancreas is producing insulin and how effectively the body is responding to it.
Main Findings
Complete insulin-related data were available for 131 participants. Compared with placebo, semaglutide produced clear metabolic benefits. Fasting glucose decreased by 0.87 mmol/L, with a 95% confidence interval from -1.15 to -0.59 and a P value of less than 0.001. This indicates a robust and statistically significant reduction in blood sugar levels.
Semaglutide also improved insulin sensitivity, meaning the body was better able to use insulin effectively. The HOMA2 insulin sensitivity measure improved significantly, with an estimate of 8.60 and a 95% confidence interval from 5.82 to 13.65; P = 0.001. In parallel, insulin resistance decreased, with a HOMA measure of -0.69 and a 95% confidence interval from -1.00 to -0.20; P = 0.006. In practical terms, this suggests that the body became less resistant to insulin’s effects, which is important for lowering the risk of progressing from prediabetes to type 2 diabetes.
Participants taking semaglutide lost an average of 9.2 kg, which is a clinically meaningful amount of weight over 30 weeks. Statistical mediation analysis suggested that this weight loss partly explained the improvement in insulin sensitivity and insulin resistance. In other words, the drug’s metabolic benefits were not only due to direct glucose-related effects, but also to the weight reduction it produced.
The study did not find a statistically significant change in β-cell function overall. There was a modest upward trend in the HOMA2 β-cell function measure, with an estimate of 8.10, but this did not reach significance (P = 0.19). Similarly, fasting insulin and C-peptide showed nonsignificant downward trends. These findings suggest that semaglutide primarily improved how the body used insulin rather than clearly increasing the pancreas’s insulin-producing capacity over the study period.
What the Results Mean
The HISTORI trial provides encouraging evidence that semaglutide may be useful beyond conventional diabetes care in people with severe mental illness who are taking antipsychotic medication. The key clinical message is that semaglutide improved glycemic control and insulin action, while also producing substantial weight loss, in a population with very high cardiometabolic risk.
This is important because antipsychotic-associated weight gain is often difficult to manage. Lifestyle measures such as diet and exercise remain essential, but they can be hard to sustain, especially when psychiatric symptoms, medication side effects, or social challenges interfere. A medication that can help reverse some of the metabolic harm may therefore be a valuable addition to care.
It is also notable that the benefits were not limited to weight loss alone. The mediation analysis showed that weight reduction explained part, but not all, of the improvement in insulin sensitivity and insulin resistance. This suggests semaglutide may have additional direct metabolic effects, consistent with its known action on appetite regulation, gastric emptying, and glucose-dependent insulin pathways.
Clinical Context
Second-generation antipsychotics, sometimes called atypical antipsychotics, are commonly used for schizophrenia and related disorders. While these medications vary in their metabolic risk, many can contribute to increased appetite, weight gain, and impaired glucose regulation. Over time, this can raise the risk of prediabetes, type 2 diabetes, dyslipidemia, and cardiovascular disease.
For clinicians, these findings support closer metabolic monitoring in psychiatric patients and reinforce the importance of early intervention when weight gain or rising glucose levels are detected. Semaglutide may be an option for selected patients, particularly those with obesity and prediabetes who have not achieved adequate results with lifestyle approaches alone.
However, treatment decisions should always be individualized. Semaglutide can cause gastrointestinal side effects such as nausea, vomiting, constipation, and diarrhea. It is also not suitable for everyone. Patients require evaluation for contraindications, consideration of drug access and cost, and coordination between psychiatric and primary care or endocrine teams.
Strengths and Limitations
A major strength of the trial is its randomized, double-blind, placebo-controlled design, which helps reduce bias and makes the findings more reliable. The study also focused on a clinically important group that is often underrepresented in metabolic trials: people with schizophrenia receiving antipsychotic treatment.
At the same time, there are limitations. The study duration was 30 weeks, which is long enough to detect meaningful short-term metabolic changes but not long enough to know whether benefits will persist over years or whether they will reduce the incidence of diabetes and cardiovascular events. The sample size was moderate, and detailed insulin data were available for fewer participants than the full randomized cohort. In addition, the trial used surrogate metabolic markers rather than direct measures like clamp studies for insulin sensitivity.
Implications for Practice
For patients with schizophrenia, prediabetes, and obesity, metabolic risk should be treated as a core part of overall care, not as a secondary issue. The HISTORI trial suggests that semaglutide can be a meaningful tool for reducing weight and improving insulin-related markers in this population.
In practice, this means clinicians may want to consider GLP-1 receptor agonists when standard lifestyle counseling is insufficient and when psychiatric treatment is otherwise stable. Careful follow-up is essential to monitor weight, blood glucose, gastrointestinal tolerance, nutritional status, and adherence to both psychiatric and metabolic therapies.
Because schizophrenia is a chronic condition and antipsychotic treatment is often necessary for long-term stability, finding ways to reduce treatment-related metabolic complications is highly relevant. Interventions that preserve mental health while improving physical health can have a major impact on quality of life and long-term outcomes.
Conclusion
In this 30-week randomized trial, semaglutide significantly improved insulin sensitivity, lowered insulin resistance, reduced fasting glucose, and led to substantial weight loss in adults with schizophrenia, prediabetes, and obesity who were taking second-generation antipsychotics. Weight loss partly mediated the metabolic improvements, while β-cell function remained largely unchanged.
These findings suggest that semaglutide may be a promising strategy for addressing antipsychotic-associated metabolic dysfunction in a high-risk population. Larger and longer studies will be needed to determine whether these benefits translate into fewer cases of diabetes, cardiovascular disease, and other long-term complications.
Reference
Ganeshalingam AA, Uhrenholt N, Arnfred S, Gæde P, Pedersen AK, Bilenberg N, Frystyk J. 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 May 1;49(5):800-807. PMID: 41778920.
