Adults who use semaglutide may have increased risk for suicidal ideation, according to results from a new case-control analysis of more than 30 million cases from the World Health Organization’s (WHO) global database of suspected adverse drug reactions (ARDs).¹

Findings showed significantly higher odds for suicidal ideation among participants who received the glucagon-like peptide-1 receptor agonist (GLP-1RA) compared with other medications for weight loss or type 2 diabetes (T2D). The trend persisted among individuals being treated simultaneously with antidepressants and benzodiazepines, researchers reported in the study published online in JAMA Network Open, August 20, 2024.¹

The results underscore a need “for urgent clarification of patient-related and drug-related risk factors,” according to investigators.¹

In June 2023, an ongoing review by the European Medicines Agency (EMA) was started after a string of reports of suicidal or self-harming thoughts associated with the use of semaglutide or liraglutide, according to researchers. Similar investigations were also announced by the British Medicines and Healthcare Products Regulatory Agency and the US FDA.¹

Preliminary data released in January 2024 by the FDA showed no evidence that GLP-1RAs cause suicidal ideations and aspirations, although the agency said it could not “definitively rule out that a small risk may exist.”² In addition, a recent retrospective analysis found that semaglutide was associated with a lower risk of first-time and recurrent suicidal ideations in patients with obesity or overweight or T2D compared with non-GLP-1RA medications.³

However, “typically, patients with suicidality are excluded from clinical trials,” first author Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, Zucker School of Medicine, Hofstra University, New York, and colleagues wrote. “Therefore, the reports from clinical trials may be less precise in capturing the risk of suicidal or self-injurious adverse drug reactions (ARDS) in later practice.”¹

Schoretsanitis and colleagues conducted the current disproportionality analysis using the WHO global database of suspected ARDs to assess potential signals for suicidal and self-injurious ARDs tied to semaglutide and liraglutide.¹

Researchers calculated the reporting odds ratio (ROR) and the Bayesian information component (IC) with 95% confidence intervals (CIs) to measure the disproportionality of reporting suicidal and self-injurious ADRs associated with the GLP-1 RAs compared to other medications. A disproportionality signal was considered significant when the lower limits of the ROR and IC were above 1 and 0, respectively. To explore potential confounders, investigators performed sensitivity analyses to examine cases with coreported use of antidepressants and benzodiazepines and to compare semaglutide and liraglutide with other drugs prescribed for similar indications, such as dapagliflozin, metformin, and orlistat.¹

Findings

Among more than 36 million total reports in the WHO database, investigators identified 107 (mean age, 48 years; 55% women) and 162 (median age, 47 years; 61% women) cases of suicidal and/or self-injurious ARDs that were reported between November 2000 and August 2023 with semaglutide and liraglutide, respectively.¹

A significant disproportionality was only observed for semaglutide-associated suicidal ideation (ROR 1.45, 95% CI 1.18-1.77; IC 0.53, 95% CI 0.19-0.78) compared with all medications. This association remained significant in patients with coreported use of antidepressants (ROR 4.45, 95% CI 2.52-7.86; IC 1.96, 95% CI 0.98-2.63) and benzodiazepines (ROR 4.07, 95% CI 1.69-9.82; IC 1.67, 95% CI 0.11-2.65) when compared with dapagliflozin (ROR 5.56, 95% CI 3.23-9.60; IC 0.70, 95% CI 0.36-0.95), metformin (ROR 3.86, 95% CI 2.91-5.12; IC 1.20, 95% CI 0.94-1.53), and orlistat (ROR 4.24, 95% CI 2.69-6.69; IC 0.70, 95% CI 0.36-0.95), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the researchers wrote.¹

Researchers noted several study limitations, including potential selection bias, limited additional adjustments for potential confounders such as alcohol use, and the inability to estimate the incidence of ARDs.¹

Based on the results, “we believe that a precaution of use in patients with psychiatric disorders or psychological lability could be added in the semaglutide package insert,” Schoretsanitis et al stated.¹

References:

1. Schoretsanitis G, Weiler S, Barbui C, Raschi E, Gastaldon C. Disproportionality analysis from World Health Organization data on semaglutide, liraglutide, and suicidality. JAMA Netw Open. Published online August 20, 2024. doi:10.1001/jamanetworkopen.2024.23385
2. US Food and Drug Administration. Update on FDA’s ongoing evaluation of reports of suicidal thoughts or actions in patients taking a certain type of medicines approved for type 2 diabetes and obesity. Preliminary evaluation does not suggest a causal link. Published online January 30, 2024. Accessed August 26, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type
3. Semaglutide linked to lower risk of suicidal ideation in patients with obesity, type 2 diabetes. News item. Sydney Jennings. January 10, 2024. Accessed August 26, 2024. https://www.patientcareonline.com/view/semaglutide-linked-to-lower-risk-of-suicidal-ideations-in-patients-with-obesity-type-2-diabetes