Semaglutide Improves Early Metabolic Abnormalities in Schizophrenia
Key Clinical Summary
- Semaglutide reduced glycemic risk in adults with schizophrenia spectrum disorders receiving clozapine or olanzapine over 26 weeks.
- Significant weight and waist reductions were observed compared with placebo, without worsening psychiatric symptoms.
- Early GLP-1RA intervention may mitigate long-term cardiometabolic complications in vulnerable psychiatric populations.
A randomized clinical trial recently published in JAMA Psychiatry evaluated adjunctive semaglutide’s effect on early metabolic abnormalities among individuals with schizophrenia spectrum disorders receiving second-generation antipsychotics (SGAs) such as clozapine or olanzapine. The multicenter Danish study assessed glycemic control, weight outcomes, and cardiometabolic risk.
Cardiometabolic comorbidity drives excess morbidity and mortality in individuals with schizophrenia spectrum disorders, particularly those treated with SGAs. These agents are linked to weight gain, insulin resistance, and type 2 diabetes, often early in treatment.
Study Findings
This double-blind, placebo-controlled randomized clinical trial enrolled 73 adults aged 18–65 in Denmark, 57 of whom completed the trial, with early glycemic dysregulation (hemoglobin A1c [HbA1c], 5.4%–7.4%) who had initiated clozapine or olanzapine within the prior 5 years. Participants were randomized to once-weekly subcutaneous semaglutide (1 mg) or matching placebo for 26 weeks, in addition to ongoing SGA therapy.
Compared with placebo, semaglutide significantly improved glycemic control: mean HbA1c reduction was −0.25% (95% CI, −0.33 to −0.16; P < .001). Approximately 43% (12 of 28) of semaglutide recipients achieved low-risk HbA1c (<5.4%) at week 26 versus 3% in the placebo group. Weight outcomes also favored semaglutide, with mean body weight reduction of 9.2 kg (95% CI, −13.3 to −5.1; P < .001), waist circumference −7.0 cm (95% CI, −10.6 to −3.3; P < .001), and fat mass −6.1 kg (95% CI, −10.2 to −1.9; P = .006).
No significant differences were seen in lipid profiles, liver function, blood pressure, or psychiatric symptom scales. Gastrointestinal adverse events occurred more frequently in the semaglutide arm but were mostly mild and transient. Psychiatric adverse events were similar between groups.
Clinical Implications
This trial supports early identification and intervention for metabolic abnormalities in psychiatric care. Improvements in HbA1c and anthropometric measures may translate to reduced long-term cardiometabolic risk. For clinicians managing patients on SGAs, incorporating GLP-1RA therapy could be considered in the context of comprehensive metabolic monitoring and management strategies. While psychiatric stability was maintained, multidisciplinary coordination between psychiatry, endocrinology, and primary care is essential when implementing such metabolic interventions.
Expert Commentary
“These results suggest that semaglutide may represent an effective strategy to mitigate the substantial metabolic burden associated with SGA treatment,” said Marie R. Sass, PhD, Mental Health Center Copenhagen, Denmark, and co-authors. “Further large-scale, long-term studies are needed to confirm these findings and explore the potential benefits of early GLP-1RA interventions on cardiovascular outcomes, addictive behaviors, and psychiatric symptomatology.”
Conclusion
This Danish randomized clinical trial indicates that semaglutide markedly improves early metabolic abnormalities in adults with schizophrenia spectrum disorders treated with SGAs. Integration of metabolic intervention strategies like GLP-1RAs may reduce long-term cardiometabolic complications, reinforcing the need for proactive metabolic care in psychiatric settings.
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