Large records study finds lower suicidal ideation among semaglutide users

Researchers analyzing electronic health records from more than 240,000 US patients with overweight or obesity reported that semaglutide was linked to a lower risk of suicidal thoughts than other anti-obesity medications, not a higher one ^[1]. The study was published in Nature Medicine on January 5, 2024, as European and US regulators were actively reviewing reports of suicidal ideation in people taking GLP-1 drugs ^[1].

What the study found

The team, led by researchers at Case Western Reserve University School of Medicine with Nora Volkow of the National Institute on Drug Abuse, used the TriNetX Analytics Network, a large database of de-identified medical records ^[1]. They compared people prescribed semaglutide (sold as Ozempic for type 2 diabetes and Wegovy for weight management) with people prescribed non-GLP-1 anti-obesity drugs: bupropion, naltrexone, orlistat, topiramate, phentermine and setmelanotide ^[1].

The main analysis covered 240,618 patients with overweight or obesity, with an average age of 50.1 years; 72.6% were female ^[1]. For the question of a first-ever episode of suicidal ideation, the analysis was limited to 232,771 patients with no prior history of it ^[1]. Over six months of follow-up, and after statistically matching the groups on their baseline characteristics, semaglutide was associated with a lower risk of first-time suicidal ideation, with a hazard ratio of 0.27, and a lower risk of recurrent suicidal ideation, with a hazard ratio of 0.44 (95% confidence interval 0.32–0.60) ^[1]. A hazard ratio below 1 means fewer events in the semaglutide group. The results held up across groupings by sex, age and ethnicity ^[1].

The researchers then repeated the analysis in a separate group of 1,589,855 patients with type 2 diabetes, average age 57.5 years and 49.2% female, comparing semaglutide with non-GLP-1 diabetes drugs. The findings were similar ^[1]. The authors concluded that their results "do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications" ^[1].

Why the question came up

In July 2023, the European Medicines Agency and the UK's Medicines and Healthcare Products Regulatory Agency opened investigations into Ozempic and Wegovy after case reports of suicidal thoughts ^[1]. The EMA review was prompted by the Icelandic Medicines Agency, which flagged reports involving Ozempic and Saxenda (liraglutide) ^[2]. The FDA's adverse event reporting system also received reports of suicidal ideation tied to semaglutide, though the study authors note those reports have not been verified ^[1].

The question was hard to settle from clinical trials alone. The trial that supported FDA approval of semaglutide for weight loss excluded people with a recent history of suicidal ideation, and the Wegovy prescribing instructions already recommend monitoring for suicidal thoughts ^[1].

Why it matters for patients

This is one of the largest looks at the question using real-world data rather than trial populations, and it included people who would have been screened out of the original trials ^[1]. But it is a retrospective study of medical records, not a randomized trial, so it can show an association and not prove cause and effect ^[1]. Follow-up was six months, so it says nothing about longer periods ^[1]. Suicidal ideation was measured by what clinicians recorded in charts, which may not capture every case. The authors did not test tirzepatide (Mounjaro, Zepbound); the comparison was semaglutide versus older weight and diabetes drugs ^[1].

The existing label guidance to watch for mood changes did not change as a result of this paper ^[2]. Whether obesity itself, weight loss, or other factors explain the lower rates seen here is not answered by the study.

What happened next

In January 2024, the FDA opened an investigation into suicidal ideation and self-harm risks with GLP-1 drugs, and about a week later a preliminary review found no evidence supporting that link ^[2]. On April 12, 2024, the EMA announced that its Pharmacovigilance Risk Assessment Committee found no causal association between GLP-1 receptor agonists and suicidal thoughts or actions, after reviewing semaglutide, liraglutide, dulaglutide and exenatide, the Nature Medicine data, and its own study ^[2]. The committee said no product information updates were required, but told manufacturers to "continue to monitor these events closely" as part of their safety activities ^[2].