Study: Disparity analysis from World Health Organization data on semaglutide, liraglutide and suicidality. Image credit: myskin / Shutterstock.com
In a recent study published in JAMA Network Openresearchers are investigating the possible link between the obesity drugs semaglutide and liraglutide and suicidal or self-injurious drug side effects.
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 such as liraglutide and semaglutide have gained popularity beyond their original purpose, which has led to global shortages.
Concerns have arisen regarding the safety of GLP-1 RAs, particularly the risk of suicidal ideation. Although regulatory agencies, including the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) have launched investigations into these risks, no definitive link between these drugs and suicide risk has been established.
The investigators of the present study aimed to investigate suicidal and self-injurious adverse drug reactions (ADRs) attributable to the use of liraglutide or semaglutide on a global scale using 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 WHO Vigibase, the largest global pharmacovigilance database comprising ICSRs from over 28 million records covering 140 countries. The study complied with ethical guidelines and did not require patient consent as the data were anonymous.
A comprehensive database search was conducted for reports related to these drugs that focused on adverse events classified as ‘suicide/self-harm’. Semaglutide reports were collected between July 2011 and August 2023, while liraglutide reports were received between November 2000 and August 2023.
Odds ratio analysis calculated the reported odds ratio (ROR) and Bayesian information component (IC) to determine whether these drugs were associated with a higher risk of these ADRs compared to other drugs. Sensitivity analyzes were also performed to account for confounding factors, such as the concomitant use of antidepressants and benzodiazepines, and to compare the findings with other drugs used to treat obesity and T2D, such as dapagliflozin, metformin, and orlistat.
Study findings
A total of 36,172,078 references 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-injury ADRs were identified for semaglutide and 162 cases for liraglutide.
The median age was 48 and 47 years for semaglutide and liraglutide users, with female patients accounting for 55% and 61% of cases, respectively. Suicidal ideation was the most common ADR reported by 88% and 71.6% of semaglutide and liraglutide users, respectively.
Suicidal ideation was found to resolve after discontinuation of the drugs in more than 50% of patients. Most patients who experienced suicidal ideation were also prescribed other medications, with antidiabetics and antidepressants being frequently mentioned.
Odds ratio analyzes showed significant signals for suicidal ideation associated with semaglutide with an ROR of 1.45 compared to other drugs. Sensitivity analyzes confirmed this finding, particularly in cases involving mood medications such as antidepressants and benzodiazepines, which are associated with an increased risk of suicidal behavior.
The trend of suicidal adverse events gradually increased over time for both drugs, thus highlighting safety concerns that require further scrutiny. These findings also highlight the importance of monitoring the safety profiles of GLP-1 receptor agonists, particularly with regard to the potential risk of suicidal and self-injurious thoughts and behaviors.
The present study is the first to use a WHO database to assess the risk of suicidal ideation possibly associated with the use of semaglutide and liraglutide. However, the study is limited by reporting barriers, inability to establish causality, lack of incidence estimates, potential biases, missing treatment effects, insufficient dose data, unaccounted for volunteer bias, pre-existing conditions, limited treatment duration data, and measures of interdependent disproportionality that affect safety interpretations.
conclusions
The study findings contribute to ongoing evaluations of the safety of liraglutide and semaglutide, particularly regarding their potential impact on suicidal behaviors.
The increasing popularity of personal reports on social media of semaglutide users may contribute to off-label use and increase public health risks, including the illicit trade in counterfeit semaglutide. Given the risk of suicidal ideation with off-label use of semaglutide, federal authorities should consider issuing warnings to inform the public of these risks.
Journal Reference:
- Schoretsanitis, G., Weiler, S., Barbui, C., et al. (2024). Disparity analysis from World Health Organization data on semaglutide, liraglutide and suicidality. JAMA Network Open 7(8). doi:10.1001/jamanetworkopen.2024.23385.
