WHO Data Indicate Semaglutide May Increase Suicidal Ideation Risk

Semaglutide – but not liraglutide – is associated with disproportionately increased reporting of suicidal ideation, according to study results published in JAMA Network.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide and liraglutide, have gained immense popularity in recent years. While these medications have demonstrated efficacy in weight management and treating type 2 diabetes, concerns over reports of suicidality associated with the medication have prompted investigations from the European Medicines Agency and the United States Food and Drug Administration (FDA).

To this aim, the current study sought to assess suicidal and/or self-injurious adverse drug reactions (ADRs) associated with liraglutide or semaglutide at the global level. Investigators conducted a disproportionality analysis using the World Health Organization (WHO) database of individual case safety reports (ICSRs) through August 30, 2023. The WHO database included ADR information collected from 140 member countries and eligible participants were clinical patients who experienced an ADR that was suspectedly attributable to either semaglutide or liraglutide. The primary outcome of interest was disproportionate reporting of suicidal and/or self-injurious ADRs associated with semaglutide and liraglutide relative to all other medications, calculated using reporting odds ratio (ROR) and the Bayesian information component (IC).

Of the 36,172,078 total ICSRs in the WHO database, 107 cases of suicidal and/or self-harm ideation were identified in association with semaglutide and 46 cases were identified in association with liraglutide. Of these suicidal and/or self-injurious ADR cases, patients taking semaglutide most commonly reported suicidal ideation (88%), followed by intentional overdose (6.5%), and suicide attempt (6.5%). Similarly, patients taking liraglutide most commonly experienced suicidal ideation (71.6%), followed by suicide mortality (11.7%), and suicide attempt (9.9%). Suicidal ideation resolved after drug discontinuation in 62.5% of the semaglutide and liraglutide cases.

The investigators observed significant disproportionality for semaglutide-associated suicidal ideation compared with all medications (ROR, 1.45; 95% CI, 1.18-1.77; IC, 0.53; 95% CI, 0.19-0.78). These findings remained significant in sensitivity analyses that included cases involving comedication with antidepressants (ROR, 4.45; 95% CI, 2.52-7.86; IC, 1.96; 95% CI, 0.98-2.63) and comedication with benzodiazepines (ROR, 4.07; 95% CI, 1.69-9.82; IC, 1.67; 95% CI, 0.11-2.65).

Similarly, the investigators found significant disproportionality for semaglutide-associated suicidal ideation 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).

However, suicidal ideation reporting was not disproportionate when excluding reports with comedications with antidepressants (ROR, 1.28; 95% CI, 1.03-1.60; IC, 0.36; 95% CI, -0.10 to 0.63), suggesting that there may be an interaction between baseline psychopathology and ADRs for semaglutide.

The investigators did not find signals for any other ADR of interest for either semaglutide or liraglutide.

These study findings demonstrate a significant disproportionality for semaglutide and suicidal ideation compared with all medications. However, the disproportionality did not remain significant when excluding cases with comedication of antidepressants, suggesting that individuals with depressive disorders may be at increased risk for semaglutide-associated suicidal ideation. “[B]ased on these findings, we believe that a precaution of use in patients with psychiatric disorders or psychological lability could be added in the semaglutide package insert,” the investigators concluded.

Study limitations include potential missing information, a lack of data on other confounders (eg, alcohol or substance use), and the inability to infer causality from the case-control design.

This article originally appeared on Psychiatry Advisor