Adjunctive use of the GLP-1 receptor agonist semaglutide was associated with greater glycemic control and better weight outcomes in patients with schizophrenia spectrum disorders, new research suggested.

In a multicenter randomized controlled trial, adults treated with clozapine or olanzapine achieved larger 26-week reductions in A1c level when once-weekly subcutaneous semaglutide was added vs matching placebo.

In addition, patients receiving adjunctive semaglutide had greater reductions in body weight, waist circumference, and fat mass.

The results support the use of the medication “as a potential early intervention strategy to reduce cardiometabolic risk in this vulnerable population,” Marie R. Sass, PhD, Mental Health Center Copenhagen, Copenhagen, Denmark, and colleagues wrote.

The findings were published online on December 3 in JAMA Psychiatry.

A Viable Risk Mitigation Strategy?

Previous research has shown that patients with schizophrenia who take second-generation antipsychotics (SGAs) have an increased risk for adverse metabolic events, including obesity and type 2 diabetes, which can lead to increased cardiovascular morbidity and mortality.

Sass and colleagues wanted to assess whether the use of a GLP-1 could help mitigate these risks. They conducted a multicenter, double-blind trial that included 73 patients with schizophrenia spectrum disorders who were between the ages of 18 and 65 years (mean age, 35 years; 65% women; mean BMI, 36.1). Participants were enrolled at three sites in Denmark from 2021 to 2024.

All had initiated treatment with clozapine or olanzapine during the previous 5 years and had early-stage glycemic dysregulation at baseline, including A1c levels of 5.4%-7.4%.

They were randomly assigned to receive once-weekly placebo (n = 37) or semaglutide (n = 36) at a starting dose of 0.25 mg that was titrated up to 1 mg from week 8 to week 26. Participants with adverse events (AEs) were maintained at a dose of 0.5 mg.

Adherence and safety were monitored at study visits conducted every 4 weeks. The primary outcome was the between-group difference in change in A1c level from baseline to week 26. A total of 78% of patients fully completed the trial.

At 26 weeks, adjunctive semaglutide produced a significantly greater A1c reduction than placebo (mean difference, -0.25%; P < .001). Low-risk A1c levels (< 5.4%) were reached by 43% of semaglutide-treated participants compared with 3% on placebo.

Results showed a significant reduction in A1c at 26 weeks for adjunctive semaglutide compared to placebo (mean difference, -0.25%; P < .001) — with 43% vs 3% achieving A1c levels of less than 5.4%.

In all sensitivity analyses models, semaglutide was associated with a greater reduction in A1c than placebo.

Body weight and waist circumference were also reduced more in the semaglutide group than in the placebo group (differences, -9.2 kg and -7 cm, respectively; P < .001 for both), as was fat mass (difference, -6.1 kg; P = .006).

Psychiatric symptoms, lipid levels, blood pressure, and liver function did not differ between the treatment groups.

Gastrointestinal events were the most common AEs, with nausea reported in 47% of the semaglutide group vs 41% of the placebo group, vomiting reported by 39% vs 14%, and constipations reported by 33% vs 19%. Serious AEs were reported by 14% vs 16% of the groups.

“These results suggest that semaglutide may represent an effective strategy to mitigate the substantial metabolic burden associated with SGA treatment,” the investigators wrote, adding that confirmatory large-scale and long-term studies are needed.

Interestingly, the findings are similar to a study published in September in JAMA Psychiatry. As reported by Medscape Medical News, its results also showed that adjunctive semaglutide treatment was linked to reduced body weight (mean difference, -9 kg) and A1c (difference, -0.46%) and better physical quality-of-life scores compared with placebo in adults with schizophrenia, prediabetes, and obesity.

The study was funded by the Mental Health Services in the Capital Region of Denmark, as well as Novo Nordisk A/S for semaglutide and semaglutide-placebo pens. Many of the investigators reported having ties with various organizations, which are fully listed in the original article.