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

Wang, William; Volkow, Nora D.; Berger, Nathan A.; Davis, Pamela B.; Kaelber, David C.; Xu, Rong

doi:10.1038/s41591-023-02672-2

Cited by 248Diabetes Treatment and ManagementPharmacology and Obesity TreatmentSuicide and Self-Harm Studies

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

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Wang, William, Volkow, Nora D., Berger, Nathan A., Davis, Pamela B., Kaelber, David C., Xu, Rong·2024·Nature Medicine

DOI 10.1038/s41591-023-02672-2PMC PMC11034947

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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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In a retrospective cohort study using TriNetX Analytics Network electronic health records, semaglutide significantly lowered the risk of new suicidal ideation compared to non-GLP-1 RA anti-obesity treatments (HR 0.27; 95% CI 0.20 to 0.32).
“in the retrospective cohort study using TriNetX Analytics Network electronic health records, semaglutide significantly lowered the risk of both new (HR, 0.27; 95% CI, 0.20 to 0.32) and recurrent (HR, 0.44; 95% CI, 0.32 to 0.60) suicidal ideation compared to non-GLP-1 RAs anti-obesity treatments [80].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [80]
The Abstract identifies a retrospective cohort study using TriNetX electronic health records, and the ‘Suicidal ideation in patients with overweight or obesity’ section reports a significantly lower risk of new suicidal ideation with semaglutide (HR 0.27) versus non-GLP1R agonist anti-obesity medications. However, that section gives the 95% CI as 0.20–0.36, not 0.20–0.32. The paper describes an association, rather than establishing that semaglutide caused the reduction. (LLM, conf=0.92)
Experimental — accuracy not yet measured
Several observational studies have generated varied findings on the effect of GLP-1 receptor agonists on the risk of suicidal ideation, self-harm, and suicide, which may be a result of methodological limitations in these studies.
“whereas several observational studies have generated varied findings on of the effect of GLP-1 receptor agonists on the risk of suicidal ideation, self-harm, and suicide, which may be a result of methodological limitations in these studies.8 9 10 11 12 13”
From Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study (2025) · cites this paper as [9]
The Discussion reports a lower association between semaglutide and suicidal ideation and describes methodological limitations inherent to observational studies, including confounding and reverse causality. It does not establish that several observational studies of GLP-1 receptor agonists had varied findings across suicidal ideation, self-harm, and suicide, or that methodological limitations explain such variation. The study says its suicide-attempt sample was too small for statistical evaluation. (LLM, conf=0.78)
Experimental — accuracy not yet measured
In the same TriNetX study, semaglutide significantly lowered the risk of recurrent suicidal ideation compared to non-GLP-1 RA anti-obesity treatments (HR 0.44; 95% CI 0.32 to 0.60).
“and recurrent (HR, 0.44; 95% CI, 0.32 to 0.60) suicidal ideation compared to non-GLP-1 RAs anti-obesity treatments [80].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [80]
Among approved anti-obesity medications, tirzepatide 15 mg and semaglutide 2.4 mg have the greatest efficacy.
“Among AOMs currently approved, tirzepatide 15 mg and semaglutide 2.4mg have the greatest efficacy (Figure 1).65,67,87”
From Approach to Obesity Treatment in Primary Care: A Review (2024) · cites this paper as [87]

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Authors: Wang, W., Volkow, N. D., Berger, N. A., Davis, P. B., Kaelber, D. C., & Xu, R.
Affiliations: Case Western Reserve University (US)
National Institutes of Health (US)
MetroHealth (US)
Corresponding author: Volkow, Nora D.
Xu, Rong
ORCID: Wang, William
Volkow, Nora D.
Berger, Nathan A.
Davis, Pamela B.
Kaelber, David C.
Xu, Rong
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2024-01
Volume: 30
Issue: 1
Pages: 168-176
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-023-02672-2
PMC: PMC11034947
OpenAlex: W4390616108
Cited by: 248
References: 34
Citations by year: 2026: 72 · 2025: 91 · 2024: 84 · 2022: 1
FWCI: 81.35
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Case Comprehensive Cancer Center, Case Western Reserve University (CA043703)
National Institute on Alcohol Abuse and Alcoholism (R01AA029831)
National Institute on Aging (R01AG061388, R56AG062272, RF1AG076649, R01AG057557)
National Cancer Institute (CA043703, CA2332216, P30CA043703, R25CA221718)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2HD084068)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
Keywords: semaglutide, suicidal ideation, GLP-1 receptor agonists, type 2 diabetes, obesity, anti-obesity drugs, drug safety, adverse drug reactions, real-world evidence
MeSH terms: Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Female, Humans, Hypoglycemic Agents, Male, Middle Aged, Obesity, Retrospective Studies, Anti-Obesity Agents, Overweight, Suicidal Ideation

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

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