Large records study links semaglutide to lower risk of suicidal ideation

A large study of electronic health records found that patients with overweight or obesity who were prescribed semaglutide had a lower risk of suicidal ideation than patients prescribed other weight-loss or diabetes medicines, researchers reported in the journal Nature Medicine on January 5, 2024 ^[1].

The research team, led by investigators at Case Western Reserve University School of Medicine and the National Institute on Drug Abuse, analyzed records from the TriNetX Analytics Network ^[1]. In the main comparison, 240,618 patients with overweight or obesity who received semaglutide were matched against patients taking anti-obesity medicines that are not GLP-1 receptor agonists: bupropion, naltrexone, orlistat, topiramate, phentermine and setmelanotide ^[1]. Over a six-month follow-up, the semaglutide group had a lower risk of first-time suicidal ideation (hazard ratio 0.27, 95% confidence interval 0.20–0.36) and of recurrent suicidal ideation (hazard ratio 0.44, 95% CI 0.32–0.60) ^[1]. The analysis of first-time events covered 232,771 patients with no prior history of suicidal ideation ^[1]. The overweight and obesity group had a mean age of 50.1 years and was 72.6% female, and the results held across sex, age and ethnicity groups, the authors wrote ^[1].

The findings replicated in a separate group of 1,589,855 patients with type 2 diabetes (mean age 57.5 years, 49.2% female), where semaglutide was compared with anti-diabetes medicines that are not GLP-1 receptor agonists ^[1]. The authors concluded that their findings "do not support higher risks of suicidal ideation with semaglutide" compared with those other medicines ^[1].

The study followed months of regulatory attention. The European Medicines Agency opened an investigation in July 2023 after the Icelandic Medicines Agency flagged reports of suicidal thoughts and self-harm in people taking Saxenda (liraglutide) and Ozempic (semaglutide) ^[2]. In the United States, the Food and Drug Administration received reports of suicidal ideation associated with semaglutide through its adverse event reporting system, although the study notes those reports have not been verified ^[1]. Wegovy's instructions include recommended monitoring for suicidal ideation, and the clinical trial that led to the drug's approval excluded participants with a recent history of suicidal ideation ^[1].

Concern about weight-loss drugs and suicide is not new. The EMA removed the weight-loss drug rimonabant from the market over reported associations with depression and suicide, and the FDA rejected Qnexa, a combination of phentermine and topiramate, partly over concerns about increased suicidal ideation ^[1].

Why it matters for patients

Reports of suicidal thoughts in people taking Ozempic and Wegovy have circulated since 2023, and the question of whether these medicines raise that risk has been a practical concern for people who take them or are considering them. This study adds a large set of real-world records, but it is an observational analysis of prescribing data and diagnoses entered into electronic health records, so it can show an association, not cause and effect ^[1]. Whether semaglutide itself lowers the risk of suicidal thoughts, or whether other differences between the patient groups explain the gap, has not been established.

The analysis covers semaglutide, which is sold as Ozempic and Wegovy for type 2 diabetes and weight loss and as Rybelsus in pill form. Results for other GLP-1 medicines have not been reported in this study. The authors also note that the trial supporting semaglutide's approval excluded people with a recent history of suicidal ideation, and that Wegovy's labeling already calls for monitoring ^[1]. The study does not address whether that monitoring should change.

What happens next

On April 12, 2024, the EMA said its Pharmacovigilance Risk Assessment Committee found no causal association between GLP-1 receptor agonists and suicidal thoughts and actions, after reviewing semaglutide, liraglutide, dulaglutide (Trulicity) and exenatide (Byetta) ^[2]. The committee said no update to the product information for GLP-1 products was required, but that companies holding marketing authorizations should continue to monitor these events closely as part of their routine safety activities ^[2]. In December 2023, the same committee had said it could not draw a definitive conclusion and asked drugmakers for more data ^[2]. The FDA opened its own investigation in January 2024 and a week later said a preliminary review found no evidence supporting a link ^[2].