Association of semaglutide with risk of suicidal ideation in a real-world cohort

Abstract

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

Extended Data Fig. 1|. Comparison of (a) recurrent suicidal ideations and (b) medication prescriptions for suicidal ideations treatments in patients with type 2 diabetes (T2DM) who had a prior history of suicidal ideations between propensity-score matched semaglutide and non-GLP1R agonist anti-diabetes medications groups for 6-month follow-up period.

For each group, overall risk (# of cases) is also shown, where overall risk is defined as the number of patients with outcomes during the 6-month follow-up period/number of patients in the cohort at the beginning of the follow-up time period.

Fig. 1|. Incident suicidal ideations in the study population with overweight or obesity.

Comparison of the incident (first-time experience of) suicidal ideation in the study population with overweight or obesity and no previous history of suicidal ideation (before the index event of the first prescription of semaglutide or non-GLP1R agonist anti-obesity medications that occurred from 1 June 2021 through to 31 December 2022) between the propensity score-matched semaglutide and non-GLP1R agonist anti-obesity medication groups within a 6-month time window after the index event. For each group, the overall risk (number of cases) is shown, where overall risk is defined as the number of patients with outcomes during the 6-month time window divided by the number of patients in the group at the beginning of the time window. HRs were calculated using Kaplan–Meier analysis to estimate the probability of outcome at daily time intervals with censoring applied.

Fig. 2|. Recurrent experience of suicidal ideation and medication prescription for suicidal ideation treatment in the study population with overweight or obesity.

a,b, Comparison of recurrent experience of suicidal ideation (a) and medication prescription for suicidal ideation treatment (b) in the study population with overweight or obesity and a previous history of suicidal ideation (before the index event of the first prescription of semaglutide versus non-GLP1R agonist anti-obesity medications that occurred from 1 June 2021 through to 31 December 2022) between the propensity score-matched semaglutide and non-GLP1R agonist anti-obesity medication groups within a 6-month time window after the index event. For each group, the overall risk (number of cases) is shown, where overall risk is defined as the number of patients with outcomes during the 6-month time window divided by the number of patients in the group at the beginning of the time window. HRs were calculated using Kaplan–Meier analysis to estimate the probability of outcome at daily time intervals with censoring applied.

Fig. 3|. Incident suicidal ideations in the study population with T2DM.

Comparison of incident (first-time experience) suicidal ideation In the study population with T2DM and no history of suicidal ideation before the index event of the first prescription of semaglutide or other non-GLP1R agonist anti-diabetes medications that occurred from 1 December 2017 through to 31 May 2021 between the propensity score-matched semaglutide and non-GLP1R agonist anti-diabetes medication groups within the 6-month time window after the index event. For each group, the overall risk (number of cases) is shown, where overall risk is defined as the number of patients with outcomes during the 6-month time window divided by number of patients in the group at the beginning of the time window. HRs were calculated using Kaplan–Meier analysis to estimate the probability of outcome at daily time intervals with censoring applied.

Fig. 4|. Incident and recurrent suicidal ideations in the study population with T2DM at different follow-up time periods.

Comparison of incident and recurrent suicidal ideation in the study population with T2DM between the propensity score-matched semaglutide and non-GLP1R agonist anti-diabetes medication groups at different follow-up time windows (up to 3 years). For each group, the overall risk (number of cases) is shown, where overall risk is defined as the number of patients with outcomes during the 6-month time window divided by the number of patients in the group at the beginning of the time window. HRs were calculated using Kaplan–Meier analysis to estimate the probability of outcome at daily time intervals with censoring applied.