Clarification urgently needed for detected signal of semaglutide-linked suicidal ideation

Study: Disproportionality Analysis From World Health Organization Data on Semaglutide, Liraglutide, and Suicidality. Image Credit: myskin / Shutterstock.com

In a recent study published in JAMA Network Open, researchers investigate the potential link between the obesity drugs semaglutide and liraglutide and suicidal or self-injurious adverse drug reactions.

The mental health effects of GLP-1 RAs

The global obesity epidemic has increased interest in glucagon-like peptide-1 receptor agonists (GLP-1 RAs), drugs originally developed for type 2 diabetes (T2D), due to their weight loss properties. GLP-1 RAs like liraglutide and semaglutide have gained popularity beyond their initial purpose, which has led to global shortages.

Concerns about the safety of GLP-1 RAs, particularly the risk of suicidal ideation, have emerged. Although regulatory agencies including the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) have initiated investigations into these risks, no definitive relationship has been established between these drugs and suicide risk.

The researchers in the present study aimed to investigate suicidal and self-injurious adverse drug reactions (ADRs) attributed to liraglutide or semaglutide use on a global scale by leveraging the World Health Organization (WHO) database of individual case safety reports (ICSRs).

About the study

The present case-control study was initiated as a disproportionality analysis of the WHO Vigibase, the largest global pharmacovigilance database that includes ICSRs from over 28 million records spanning 140 countries. The study adhered to ethical guidelines and did not require patient consent, as data were anonymized.

A comprehensive search of the database was conducted for reports related to these drugs that focused on ADRs classified under ‘suicide/self-injury.’ Semaglutide reports were collected between July 2011 and August 2023, whereas liraglutide reports were obtained between November 2000 and August 2023.

Disproportionality analysis calculated the reporting odds ratio (ROR) and Bayesian information component (IC) to determine whether these drugs were associated with a higher risk of these ADRs as compared to other medications. Sensitivity analyses were also performed to account for confounding factors, such as the concomitant use of antidepressants and benzodiazepines, as well as compare the findings with other drugs used for obesity and T2D treatment, like dapagliflozin, metformin, and orlistat.

Study findings

A total of 36,172,078 reports were analyzed for the current study. The primary indication for prescribing both liraglutide and semaglutide was potential off-label use, followed by weight management and diabetes treatment. A total of 107 cases of self-injurious ADRs for semaglutide and 162 cases for liraglutide were identified.

The median age was 48 and 47 years for semaglutide and liraglutide users, with female patients representing 55% and 61% of the cases, respectively. Suicidal ideation was the most prevalent ADR that was reported by 88% and 71.6% of semaglutide and liraglutide users, respectively.

Suicidal ideation was found to resolve after discontinuing the drugs in over 50% of patients. Most patients who experienced suicidal ideation were also prescribed other medications, with antidiabetics and antidepressants frequently co-reported.

Disproportionality analyses indicated significant signals for semaglutide-associated suicidal ideation with an ROR of 1.45 as compared to other medications. Sensitivity analyses confirmed this finding, particularly in cases involving comedications such as antidepressants and benzodiazepines, which are associated with an increased risk of suicidal behavior.

The trend of suicidal ADRs gradually increased over time for both drugs, thus highlighting safety concerns that require further scrutiny. These findings also emphasize the importance of monitoring the safety profiles of GLP-1 receptor agonists, particularly concerning the potential risk of suicidal and self-injurious thoughts and behaviors.

The present study is the first to leverage a WHO database to assess the suicidal ideation risk potentially associated with semaglutide and liraglutide use. However, the study is limited by reporting barriers, inability to establish causality, lack of incidence estimates, potential biases, missing treatment outcomes, insufficient dose data, unaccounted volunteer bias, pre-existing conditions, limited treatment duration data, and interdependent disproportionality measures that affect safety interpretations.

Conclusions

The study findings contribute to ongoing assessments of the safety of liraglutide and semaglutide, particularly concerning their potential impact on suicidal behaviors.

The growing popularity of personal reports on social media of semaglutide users may contribute to off-label use and increase public health risks, including the illegal trade of counterfeit semaglutide. Given the associated risk of suicidal ideation with off-label semaglutide use, federal authorities should consider issuing warnings to inform the public about these risks.