According to a new study published in JAMA Psychiatry, adjunctive semaglutide was shown to significantly improve glycemic control and weight outcomes in individuals with schizophrenia spectrum disorders receiving second-generation antipsychotics (SGAs), establishing early in the study that this treatment may reduce long-term cardiometabolic risk in a high-risk population. Individuals treated with SGAs such as clozapine and olanzapine often develop obesity, prediabetes, and type 2 diabetes, leading to markedly increased cardiovascular morbidity and premature mortality. This study was conducted by Marie R. and colleagues.
This multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted across 3 clinical sites in Denmark between September 2021 and August 2024. Participants aged 18–65 years with schizophrenia spectrum disorders were eligible if they had begun clozapine or olanzapine within the previous 5 years and displayed early glycemic dysregulation, defined by HbA1c 5.4%–7.4%. None were on antidiabetic medications at enrollment. A total of 104 individuals were screened, 73 were randomized, and 57 (78%) completed the 26-week follow-up. Participants received once-weekly semaglutide 1 mg or a matched placebo in addition to their SGA regimen. The primary outcome was the change in HbA1c from baseline to week 26, analyzed using the intention-to-treat approach. Secondary outcomes assessed weight, waist circumference, fat mass, metabolic parameters, and psychiatric status.
Results
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73 randomized; 57 (78%) completed the trial
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Semaglutide reduced HbA1c significantly: −0.25% (95% CI, −0.33 to −0.16)
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43% achieved HbA1c <5.4% vs 3% with placebo
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Weight change: −9.2 kg (95% CI, −13.3 to −5.1 kg; P < .001)
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Waist circumference: −7.0 cm (95% CI, −10.6 to −3.3; P < .001)
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Fat mass reduction: −6.1 kg (95% CI, −10.2 to −1.9; P = .006)
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No significant differences in psychiatric symptoms or laboratory markers for risk
This randomized clinical trial demonstrated that adjunctive semaglutide significantly improved glycemic control, body weight, waist circumference, and fat mass in individuals with schizophrenia spectrum disorders receiving SGAs, without adversely affecting psychiatric stability.
Reference:
Sass MR, Klausen MK, Schwarz CR, et al. Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders: A Randomized Clinical Trial. JAMA Psychiatry. Published online December 03, 2025. doi:10.1001/jamapsychiatry.2025.3639