Is There a Link Between Semaglutide and Suicidal Ideation?

Georgios Schoretsanitis, MD, PhD

Credit: ResearchGate

A recent study using data from the World Health Organization (WHO) global database showed a possible association between semaglutide and suicidal ideation.

Semaglutide and liraglutide, originally marketed as diabetes medications, have gained popularity in recent years because of their weight loss benefits, leading to a global shortage of the drugs. Despite the reported benefits, some concerns over their safety have been raised.

In July 2023, the European Medicines Agency (EMA) conducted a review based on reports indicating a potential link between liraglutide and semaglutide treatment and suicidal or self-harming thoughts.

“The EMA-led investigation might have a global impact, given that liraglutide and semaglutide are administered to more than 20 million people per year,” wrote a team of investigators led by Georgios Schoretsanitis, MD, PhD, associated with the Zucker Hillside Hospital, Department of Psychiatry, at Northwell Health. “So far both EMA and US Food and Drug Administration (FDA) declared that they did not find any clear demonstration of a relationship between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicide based on the available evidence, although the FDA investigation is still ongoing.”

To evaluate this link, investigators conducted a disproportionality analysis using suspected adverse drug reactions reported in the WHO database. The global database is the largest pharmacovigilance archive, comprised of over 28 million reports of suspected adverse drug reactions from 140 countries.

Included patients experienced an adverse reaction that could be attributed to semaglutide or liraglutide between November 2000 and August 2023. Although investigators categorized indications (diabetes, weight management, possible off-label indications and others), patients were eligible for analysis regardless of indication or treatment duration.

A total of 107 cases of suicidal and/or self-injurious adverse reactions were identified among patients receiving semaglutide, with a median age of 48 years and 55% were female. A total of 162 patients, median age 47 years and 61% female, were in the liraglutide group. The median treatment duration was 24 days in the semaglutide cohort and 46 days in the liraglutide cohort.

Across groups, the main reason for prescription was possible off-label use (31.8% in the semaglutide group and 33.9% in the liraglutide group), followed by weight management (26.2% and 24.7%, respectively) and diabetes (24.3% and 20.4%, respectively).

Results revealed a disproportionality signal of suicidal ideation with semaglutide. This association maintained significance even when comparing semaglutide with metformin and dapagliflozin, as well as in the subgroup analysis of patients who were concurrently treated with benzodiazepines and antidepressants.

Suicidal ideation resolved after discontinuing the drug in 62.5% of cases across treatment arms. Suicidal ideation, suicide attempt and intentional overdose were more common among patients in the semaglutide group (88%, 6.5% and 6.5%, respectively). In the liraglutide group, suicidal ideation, completed suicide and suicide attempt were reported in 71.6%, 11.7% and 9.9% of patients, respectively. Suicidal ideation was more commonly reported in older patients prescribed liraglutide for diabetes compared with weight management and off-label indications.

Investigators noted potential limitations due to reporting issues and missing information. Additionally, they could not estimate the incidence of adverse drug reactions because of the lack of a denominator. There is also a chance of volunteer bias due to the absence of sociodemographic information. Lastly, investigators mentioned the possibility that suicidal ideation may have preexisted treatment with a GLP-1 RA.

“Our findings are relevant to the general reader seeking up-to-date information,” investigators wrote. “This relevance arises from the expectation that personal or anecdotal reports may continue to gain popularity on social media platforms without knowledge about risks…Considering the risk of suicidal ideation in people taking semaglutide off-label, authorities should consider issuing a warning to inform about this risk.”