Study reignites debate on GLP-1 drugs and suicide risk

A study has found a higher risk of suicidal thoughts in users of Novo Nordisk's GLP-1 agonist-based drugs for diabetes and obesity, even though regulators in the US and EU concluded there was no evidence for a link.

The observational study published in JAMA Network Open used the World Health Organization (WHO) global database of suspected adverse drug reactions, called VigiBase, to look at signals for suicidal and self-harm thinking among users of Novo Nordisk's semaglutide and liraglutide products up to the end of August last year.

The authors found "significant disproportionality" with semaglutide, the active ingredient in Novo Nordisk's diabetes drug Ozempic and Wegovy for obesity, but not for liraglutide or other commonly prescribed diabetes drugs, and concluded this "warrants urgent clarification."

In a nutshell, they found that a person taking semaglutide was 1.45 times more likely to mention suicidal ideation compared to patients on dapagliflozin, metformin, or orlistat, rising to 4.45 times in people also taking antidepressants and around 4.07 times in people also on benzodiazepines.

The authors acknowledge that the results cannot indicate causality, and could have been biased because the database relies on doctors and patients self-reporting symptoms and doesn't give an indication of how long a patient has been taking the drugs or other variables like alcohol or substance misuse.

It should also be noted that, while the WHO's database is huge, with 28 million reports from 140 countries, the number of reports of suicidal ideation with semaglutide was low, at 94, suggesting that even if confirmed it would be a very rare, albeit serious, side effect.

One commentator on the study, pharmacoepidemiology specialist Stephen Evans of the London School of Hygiene and Tropical Medicine, said that the study has major limitations, including that self-reported side effects "are very subject to bias, including effects of media reporting."

He said that it is not possible to conclude from the study that semaglutide itself is responsible for suicidality, but added: "There are other grounds, based on previous evidence and with other drugs, for being cautious in the use of semaglutide, and being aware of patients' mental health when prescribing it is sensible, even though semaglutide itself seems not to increase mental health problems."

The study comes after an EMA review of GLP-1 drugs for diabetes and obesity concluded in April that there was no evidence of an increased risk of suicidal or self-injurious thoughts and actions, a finding in line with the FDA which also said it found no link in an initial appraisal published in January. Both regulators have, however, said they are continuing to monitor adverse events with the drug class.

Dr Nerys Astbury, a diet and obesity specialist at the University of Oxford, who was not involved in the study, said: "Whilst the findings reported here are observational, and cannot infer causality, they send a clear message that there is a lot still to be learnt about the newer classes of obesity mediations."

She added: "These results suggest further close investigation is needed to explore possible effects of GLP-1 agonists, now popular weight loss medications, on adverse mental health outcomes."

Balanced against the potential risk of semaglutide and other GLP-1 drugs is the increasing number of studies finding benefits beyond diabetes and weight loss, including reduction of cardiovascular risk, prevention of chronic kidney disease complications, reductions in obesity-related cancers, and most recently prevention of diabetes in overweight prediabetic individuals.

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