Clarification of detected signals of suicidal ideation associated with semaglutide is urgently needed

study: Disproportionality analysis from World Health Organization data on semaglutide, liraglutide and suicidalityImage credit: myskin / Shutterstock.com

In a recently published study, JAMA Network OpenResearchers are investigating a potential link between the obesity drugs semaglutide and liraglutide and adverse drug reactions that lead to suicide or self-harm.

The impact of GLP-1 RA on mental health

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

Concerns have emerged regarding the safety of GLP-1 RAs, particularly the risk of suicidal ideation, and although regulatory agencies such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have initiated investigations into these risks, no clear link has been established between these medications and suicide risk.

The study researchers aimed to investigate global adverse drug reactions (ADRs) of suicide and self-harm associated with the use of liraglutide or semaglutide, utilising the World Health Organization's (WHO) Individual Case Safety Report (ICSR) database.

About the Research

The case-control study was initiated as a disproportionality analysis of WHO Vigibase, the world's largest pharmacovigilance database containing more than 28 million ICSRs across 140 countries. The study complied with ethical guidelines and patient consent was not required as data were anonymized.

A comprehensive search of databases was performed for reports focusing on ADRs classified as “suicide/self-harm” related to these drugs. Reports for semaglutide were collected between July 2011 and August 2023, whereas reports for liraglutide were retrieved between November 2000 and August 2023.

In disproportionality analyses, reporting odds ratios (RORs) and Bayesian information components (ICs) were calculated to determine whether these medications were associated with a higher risk of these ADRs compared with other medications. Sensitivity analyses were also performed to account for confounding factors, such as concomitant use of antidepressants and benzodiazepines, and to compare the results with other medications used to treat obesity and type 2 diabetes, such as dapagliflozin, metformin, and orlistat.

Research findings

A total of 36,172,078 reports were analysed in the study. The main indication for prescribing both liraglutide and semaglutide was potential off-label use, followed by weight control and diabetes treatment. A total of 107 self-harm ADRs were identified for semaglutide and 162 for liraglutide.

The mean age of semaglutide and liraglutide users was 48 and 47 years, and female patients accounted 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.

The researchers found that suicidal thoughts resolved after stopping the medication in more than 50% of patients. Most of the patients who experienced suicidal thoughts were also prescribed other medications, and many reported being prescribed antidiabetic and antidepressant medications at the same time.

Disproportionality analysis showed a significant indication of suicidal ideation associated with semaglutide, with an ROR of 1.45 compared with other medications. Sensitivity analyses confirmed this result, especially in cases involving concomitant medications such as antidepressants and benzodiazepines, which are associated with an increased risk of suicidal behavior.

Both drugs have shown a gradual increase in suicide-related side effects over time, highlighting safety concerns that require further investigation. These findings also highlight the importance of monitoring the safety profile of GLP-1 receptor agonists, particularly the potential risk of suicide and self-harm.

This is the first study to utilize the WHO database to assess the risk of suicidal ideation potentially associated with semaglutide and liraglutide use. However, it is limited by reporting barriers, inability to establish causality, lack of incidence estimates, potential bias, missing treatment outcomes, insufficient dosing data, unaccounted for volunteer bias, pre-existing medical conditions, limited treatment duration data, and interdependent imbalance indicators that affect safety interpretation.

Conclusion

The findings will contribute to the ongoing evaluation of the safety of liraglutide and semaglutide, particularly their potential effect on suicidal behaviour.

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