NIH study: Semaglutide associated with lower risk of suicidal ideation

Semaglutide is associated with a 49─73 percent lower risk of suicidal ideation vs other agents for treatment of obesity and type 2 diabetes mellitus (T2DM), a National Institutes of Health (NIH)─funded study has shown.

Semaglutide is a widely used glucagon-like peptide 1 receptor agonist (GLP-1 RA). Its weight-loss and cardio-protective effects are established in the SELECT trial in obesity patients without diabetes and the SUSTAIN-6 trial in T2DM patients. [J Investig Med 2022;70: 5-13; N Engl J Med 2023;389:2221-2232; N Engl J Med 2016;375:1834-1844]

“Concerns over reports of suicidal ideation in patients prescribed semaglutide have spurred the European Medicines Agency [EMA] to investigate the potential association,” wrote the researchers. “However, the association had not yet been explored in [any] comprehensive studies.”

In a nationwide retrospective study, the researchers analyzed electronic health records in the US from >1.8 million patients prescribed semaglutide or non─GLP-1 RA between December 2017 and May 2021, including 240,618 overweight or obese patients (mean age, 50.1 years; female, 72.6 percent) and 1,589,855 T2DM patients (mean age, 58 years; female, 49.2 percent). After propensity score matching, the semaglutide and non─GLP-1 RA groups were balanced in terms of baseline characteristics (ie, age, gender, ethnicity). The follow-up period of the main analysis was 6 months. [Nat Med 2024;doi:10.1038/s41591-023-02672-2]

Patients in the non─GLP-1 RA group were prescribed agents including bupropion, naltrexone, orlistat, topiramate, phentermine and setmelanotide for obesity treatment, as well as insulin, metformin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors for T2DM treatment.

In the overweight or obesity cohort, semaglutide significantly lowered the risks of incident and recurrent suicidal ideation vs non─GLP-1 RA (incident: 0.11 percent vs 0.43 percent; hazard ratio [HR], 0.27; 95 percent confidence interval [CI], 0.20–0.36) (recurrent: 6.5 percent vs 14.1 percent; HR, 0.44; 95 percent CI, 0.32–0.60). Consistent risk reductions were seen regardless of gender, age and ethnicity.

Similar findings were observed in the T2DM cohort, in which semaglutide was associated with significantly lower risks of incident and recurrent suicidal ideations vs non─GLP-1 RA (incident: 0.13 percent vs 0.36 percent; HR, 0.36; 95 percent CI, 0.25–0.53) (recurrent: 10.0 percent vs 17.9 percent; HR, 0.51; 95 percent CI, 0.31–0.83) after 6 months of follow-up.

“We extended follow-up to 3 years in the T2DM cohort. Results showed consistently lower risks with semaglutide vs non─GLP-1 RA in both incident [HR, 0.58; 95 percent CI, 0.49–0.72] and recurrent [HR, 0.58; 95 percent CI, 0.40–0.83] suicidal ideation,” reported the researchers.

The differences in actual suicide attempts were not evaluable as the sample size was too small (n<10) for statistical evaluation.

“[Contrary to the claims of anecdotal reports], our results do not support the concern about increased suicidal risk associated with semaglutide raised by the EMA and Medicines and Healthcare Products Regulatory Agency in the UK,” remarked the researchers. “This highlights the need for more detailed evaluation of the previously reported cases.”