Semaglutide as a Dual Solution for Psychiatric and Metabolic Care

All-cause mortality rates are more than three-fold higher in patients with schizophrenia, including a three-fold increased risk of death from Type 2 diabetes and a two-fold increased risk of death from cardiovascular disease. A new clinical trial published in JAMA Psychiatry provides strong evidence that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that is given once a week, may help control metabolic risk factors in patients who are at high risk.

People with schizophrenia have a far shorter life expectancy than the normal population, frequently by 15 years. The main reasons for this big difference are cardiovascular disease and obesity-related Type 2 diabetes. While modifiable factors such as diet and physical inactivity play a role, second-generation antipsychotics for symptom control can exacerbate these risks by promoting weight gain and metabolic dysfunction. Existing weight loss and metabolic interventions in this patient group have previously shown limited effect.

Ashok A. Ganeshalingam, M.D.

Ashok A. Ganeshalingam, M.D., from the Department of Endocrinology, Odense University Hospital, Odense, Denmark, and colleagues led the Home-based Intervention With Semaglutide Treatment Of Neuroleptic-Related Prediabetes (HISTORI) trial (NCT05193578).

The trial evaluated semaglutide in adults with schizophrenia and prediabetes who were overweight or obese and who were prescribed second-generation antipsychotics. This trial was conducted in Denmark from 2022 to 2024. The study included 154 adults (mean age 38 years) with schizophrenia spectrum disorders, prediabetes, and BMI ≥27, who were stable on antipsychotic therapy. Semaglutide was titrated to 1.0 mg weekly over 8 weeks and compared with placebo for 30 weeks. The primary outcome was change in HbA1c and the secondary outcomes included body weight, metabolic markers, schizophrenia symptoms, and quality of life.

Researchers found that semaglutide significantly improved both glycemic control and body weight. Semaglutide reduced HbA1c by 0.46% compared with placebo. Importantly, 81% of treated patients achieved normal glycemic levels compared with only 19% in the placebo group. Patients lost an average of 9.2 kg (20 lbs.) more than placebo, with significant reductions in waist and hip circumference.

Improvements were observed in lipid profiles, with high-density cholesterol (HDL) increasing by 10.81 mg/dL and triglycerides decreasing by 29.20 mg/dL. There were no changes in total cholesterol, LDL, systolic and diastolic blood pressure.

Gastrointestinal side effects were more common but manageable. Serious adverse events did not differ between groups.

From a quality-of-life standpoint, semaglutide substantially enhanced physical quality of life. Semaglutide did not significantly affect mental quality of life scores demonstrating that the intervention did not deteriorate mental health.

Weight gain and metabolic side effects are two of the main reasons why people don’t stick to second-generation antipsychotics. This typically leads to relapse, hospitalization, and increased overall care costs. Semaglutide may indirectly improve adherence to mental therapy and lower expensive acute episodes by preventing weight gain and increasing physical health.

Ganeshalingam and colleagues determined that due to the notable advantages noted, specifically the reduction of blood glucose levels, weight loss, enhancement of metabolic parameters and improvement of physical quality of life without exacerbating psychiatric symptoms, semaglutide should be considered for individuals with schizophrenia, prediabetes and a body mass index of 27 or greater.

Although semaglutide carries a high upfront drug cost, the potential to avert diabetes progression, reduce cardiovascular events, and improve adherence to antipsychotics may yield favorable cost offsets. Payers may consider targeted coverage for high-risk subgroups, such as patients treated with antipsychotics and who have prediabetes and obesity, where the return on investment is most compelling.