(SLC-042) Characterizing Neuropsychiatric Adverse Events of Semaglutide Reported in FAERS: Analysis of Off-Label and On-Label Use

Background: A 256% increase from 2018 to 2022 in off-label use of semaglutide is unprecedented. This calls for consideration of the potential risks, especially given the lack of clinical trials for off-label indications. Recent concerns about neuropsychiatric adverse events (NPAEs) with semaglutide have not been evaluated with respect to patient characteristics, seriousness, and off-label use, but these reported events warrant investigation.

Objectives: To assess the frequency, demographic characteristics, seriousness, and off-label use of reported NPAEs associated with semaglutide.

Methods: We conducted a pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database from 12/05/2017 to 09/30/2024. All reports related to NPAEs were identified during this time. For this analysis, the data elements extracted from the FAERS database included suspect product name, reason for use, type of reaction, seriousness, outcomes of reactions, sex of the individual, and patient age. We categorized NPAEs into 38 categories based on the Medical Dictionary for Regulatory Activities Classification System. The data were stratified by age (≤18, 19-64, and ≥ 65 years old), sex, off-label vs. on-label, seriousness, and outcomes. Pearson’s chi-squared test was used for bivariate comparisons. Time trend analysis of the number of reports per year was analyzed using a Poisson regression model.

Results: Among 37,694 semaglutide AEs, 24.95% were NPAEs, reported in 6,832 patients. Females accounted for 68.59% of NPAEs, and 59.35% were in adults 19-64 years old. NPAEs increased from 119 reports in 2018 to 2,323 in 2024. The trend analysis was significant, revealing the case reports were 1.55 times higher (95% confidence interval: 1.53-1.57) for each additional year across the study period. More than half of the reported NPAEs were associated with off-label use (53.16%) and 38.63% were serious. Commonly reported NPAEs included headache (14.62%), dizziness (11.36%), anxiety (4.38%), depression (3.86%), insomnia (3.32%), suicidal ideation (3.07%), taste disorder (2.24%), loss of consciousness (2.19%), tremor (2.19%), and paresthesia (2.14%). Reports of headache and anxiety were significantly more likely with off-label use compared to on-label use (p < 0.001).

Conclusions: An increase in reporting of NPAEs with semaglutide, particularly with off-label use, highlights the importance of considering the potential risks for anxiety, depression, insomnia, and suicidal ideation. Rigorous studies using real-world data are needed to characterize semaglutide’s risk profile related to NPAEs, paving the way for safer prescribing practices and guiding regulatory oversight.