Semaglutide Shows Safety in Patients with Schizophrenia, Prediabetes, Obesity

A recent study showed that 30 weeks of semaglutide administration, up to 1.0 mg/week, was safe among patients with schizophrenia, prediabetes, and obesity.¹

“Semaglutide significantly reduced HbA1C, body weight, and metabolic variables and improved physical [quality of life] without affecting mental status,” wrote study investigator Ashok A. Ganeshalingam, MD, from Odense University Hospital in Denmark, and colleagues.¹

Patients with schizophrenia face reduced life expectancy from cardiovascular disease and obesity-related diabetes, risks often worsened by second-generation (SGA) antipsychotics. Existing treatments offer limited effectiveness in managing schizophrenia and mitigating these risks.

Ganeshalingam and colleagues sought to assess the effect of once-weekly semaglutide, a glucagon-like peptide-1 receptor agonist, in 154 patients aged 18 – 60 years (mean age, 38.3 years; 56.5% females) with schizophrenia, prediabetes, and obesity treated with second-generation antipsychotic medication. The study identified prediabetes as glycosylated hemoglobin A1C [HbA1C], 5.7%-6.4% of total hemoglobin, and overweight or obesity as a body mass index (BMI) of ≥ 27.¹

The primary outcome was the change in HbA1c. Secondary outcomes 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).

The team conducted a placebo-controlled, double-blinded, randomized clinical trial from January 2022 to May 2020, involving participants from regional community-based mental health services in 2 Danish regions: Region of Southern Denmark and Region of Zealand. Investigators randomized participants to semaglutide (titrated up to 1.0 mg/week) or placebo over 8 weeks. The study included a 30-week follow-up, and data were analyzed between May 2024 and January 2024.

The study found that semaglutide reduced HbA1c by 0.46% of total hemoglobin (95% confidence interval [CI], -0.56% to – 0.36%) and body weight by 9.21 kg (95% CI, -11.68 to -6.75).¹

Investigators noted that they observed less weight loss than in the SELECT trial (7.5% vs 8.5%). SELECT evaluated semaglutide 2.4 mg/week versus placebo over 104 weeks in obese individuals without diabetes.²

“The difference may be attributed to the higher semaglutide dose and longer treatment duration in the SELECT trial,” investigators explained.¹ “Since the cardiovascular risk reduction in the SELECT study was primarily driven by weight loss, we believe weight management — for instance, via treatment with a GLP-1RA — should be part of the preventive intervention for CVD in patients with [schizophrenia spectrum disorders] with antipsychotics-induced prediabetes.”

Additionally, 81% of patients on semaglutide vs 19% on placebo achieved an HbA1c < 5.7% of total hemoglobin (P < .001). The study also observed patients on semaglutide had improved high-density cholesterol by 10.81 mg/dL (95% CI, 2.7-18.53; P = .007) and triglycerides by -29.20 mg/dL (95% CI, -55.75 to 2.65; P = .03).¹

Moreover, semaglutide improved physical quality of life by 3.75 points on the SF-36v2 (95% CI, 1.52 to 5.98; P = .001). Semaglutide showed no significant effect on mental quality of life scores or PANSS-6 scores.¹

Investigators noted more gastrointestinal symptoms in patients treated with semaglutide. Patients treated with semaglutide were hospitalized more frequently than those treated with placebo, but the number of serious adverse events did not differ between arms.

HbA1c results were comparable to the SELECT study. Baseline HbA1C was similar between studies (5.78% in SELECT), and HbA1C reductions were also comparable (0.32% vs 0.46%).¹ This suggests that in SGA-treated patients with schizophrenia, 30 weeks of semaglutide 1 mg/week may achieve HbA1C improvements similar to 104 weeks of semaglutide 2.4 mg/week.

“On this basis, we speculate that overweight or obese patients without diabetes with [schizophrenia] and SGA treatment have an increased responsiveness to semaglutide, but whether this is caused by reductions in the adverse effects of SGA (eg, appetite) or the psychiatric disease per se remains unknown,” investigators wrote.¹

In addition to lowering HbA1c, semaglutide reduced the proportion of patients with prediabetes by 4-fold—a finding not previously seen in earlier exenatide studies. Investigators emphasize that this finding is clinically meaningful and should inform the management of high-risk patients with schizophrenia to help prevent cardiovascular disease.¹

“Given these benefits, semaglutide should be considered for patients with [schizophrenia], prediabetes, and a BMI of 27 or higher, as the potential for weight loss and prevention of T2D may justify the economic cost of treatment,” investigators concluded.¹

References

1. Ganeshalingam AA, Uhrenholt N, Arnfred S, et al. Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial. JAMA Psychiatry. Published online September 3, 2025. doi:10.1001/jamapsychiatry.2025.2332

2. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563