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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.

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Fig. 1: Incident suicidal ideations in the study population with overweight or obesity.
Fig. 2: Recurrent experience of suicidal ideation and medication prescription for suicidal ideation treatment in the study population with overweight or obesity.
Fig. 3: Incident suicidal ideations in the study population with T2DM.
Fig. 4: Incident and recurrent suicidal ideations in the study population with T2DM at different follow-up time periods.

Data availability

This study used population-level aggregate and de-identified data collected by the TriNetX Platform, which are available from TriNetX (https://trinetx.com/); however, third-party restrictions apply to the availability of these data. The data were used under license for this study with restrictions that do not allow for data to be redistributed or made publicly available. To gain access to the data, a request can be made to TriNetX (join@trinetx.com), but costs might be incurred and a data-sharing agreement would be necessary. Data specific to this study, including diagnosis codes and group characteristics in aggregated format, are included in the paper as tables, figures and supplementary files.

Code availability

All the statistical analyses in this study, including propensity score matching and Kaplan–Meier survival analyses were conducted using the TriNetX platform with its built-in functions. The data and code needed to reproduce the analyses can be accessed at https://github.com/bill-pipi/semaglutide_suicide.

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Acknowledgements

We acknowledge support from the National Institute on Alcohol Abuse and Alcoholism (no. AA029831), the National Institute on Aging (nos. AG057557, AG061388, AG062272 and AG07664) and the National Cancer Institute Case Comprehensive Cancer Center (nos. CA221718, CA043703 and CA2332216). The funding sources had no role in the design, execution, analysis, data interpretation or decision to submit the results of this study.

Author information

Authors and Affiliations

Authors

Contributions

R.X. conceived the study. R.X. and N.D.V. designed the study. W.W. performed the data analysis and created the tables and figures. R.X. and N.D.V. interpreted the results and drafted the paper. N.A.B., P.B.D. and D.C.K. critically contributed to study design, result interpretation and paper preparation. R.X. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Nora D. Volkow or Rong Xu.

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The authors declare no competing interests.

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Nature Medicine thanks Chiara Gastaldon, Hongjiang Wu and Tanja Stamm for their contribution to the peer review of this work. Primary Handling Editor: Ming Yang, in collaboration with the Nature Medicine team.

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Extended data

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.

Extended Data Table 1 Characteristics of the semaglutide and non-GLP1R agonists anti-obesity medications groups for patients with overweight or obesity who had a prior history of suicidal ideations
Extended Data Table 2 Characteristics of the semaglutide and non-GLP1R agonists anti-diabetes medications groups for the study population of patients with T2DM who had a prior history of suicidal ideations
Extended Data Table 3 Clinical diagnosis, medications, procedures, and other codes

Supplementary information

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Wang, W., Volkow, N.D., Berger, N.A. et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med 30, 168–176 (2024). https://doi.org/10.1038/s41591-023-02672-2

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