GLP-1 Receptor Agonists and Suicide Risk in a Nationwide Study
Key Takeaways
- In these Danish cohorts, GLP-1 receptor agonist initiation was not linked to a higher adjusted hazard versus SGLT-2 inhibitors after 1 year of follow-up and was associated with a lower adjusted hazard versus DPP-4 inhibitors.
- Within-person analyses showed lower incidence during exposed periods than during the pretreatment reference period.
- Overall findings did not show increased incidence, although observational limits and low event counts remain important when interpreting the results.
The analysis used two new-user, active-comparator cohorts and a self-controlled case series to study suicide or suicide attempts. One cohort compared GLP-1 receptor agonists in 83,464 new users with SGLT-2 inhibitors in 78,366 users, and the other compared GLP-1 receptor agonists in 108,322 users with DPP-4 inhibitors in 55,411 users. In intention-to-treat analyses, cohort follow-up continued through 31 December 2022; in as-treated analyses, a gap longer than 90 days between prescription fills marked treatment end. The analyses adjusted for measured sociodemographic and clinical factors, accounted for competing risk of death, and used the within-person design as a complementary check.
In the active-comparator cohorts, the adjusted HR for suicide or suicide attempts after 1 year of follow-up was 0.93 (95% CI, 0.57-1.52) versus SGLT-2 inhibitors and 0.58 (95% CI, 0.37-0.91) versus DPP-4 inhibitors. In intention-to-treat analyses, median follow-up was 1 year [1-3] for GLP-1 users and 2 years [1-3] for SGLT-2 users. Median follow-up was 2 years [1-4] for GLP-1 users and 4 years [2-7] for DPP-4 users in the second cohort. Overall, the active-comparator results did not suggest a higher hazard.
The self-controlled case series used the 12 months before treatment initiation as the reference period and compared it with 0-12 months and 13-24 months after initiation. During the first exposed window, the incidence rate ratio for suicide or suicide attempts was 0.45 (95% CI, 0.10-0.50). The later exposed period was also lower than pretreatment, although the exact estimate was not provided in the available text. Sensitivity analyses by recent psychiatric history and interaction testing by sex, age, and prior suicide attempts did not change the overall no-increase pattern, aside from one interaction involving prior attempts and sex in the SGLT-2 comparison.
The authors noted several limitations, including possible exposure misclassification because adherence was not directly measured and residual confounding despite adjustment. Low numbers of suicide and suicide attempt events limited precision, and competing risk of death could have led to underestimation. Time-varying factors could still affect the self-controlled analysis, and obesity subgroup assessment was limited by underreporting in Danish registries. Across both analytic approaches, GLP-1 receptor agonist use was not associated with increased incidence of suicide or suicide attempts in this Danish registry setting.
Frequently Asked Questions
What are the psychiatric and suicide-risk findings for GLP-1 receptor agonists?
In a nationwide Danish registry study using two active-comparator new-user cohorts and a self-controlled case series, GLP-1 receptor agonist initiation was not associated with an increased incidence of suicide or suicide attempts. After 1 year of follow-up, the adjusted hazard ratio was 0.58 (95% CI 0.37-0.91) versus DPP-4 inhibitors and 0.93 (95% CI 0.57-1.52) versus SGLT-2 inhibitors. The within-person self-controlled case series showed an incidence rate ratio of 0.45 (95% CI 0.10-0.50) in the first 12 months after initiation versus the 12 months before. Across both analytic approaches, no increased incidence was observed, although low event counts, residual confounding, and competing risk of death are important interpretive limits.
What's the latest on GLP-1 receptor agonists for obesity and weight management?
For obesity and weight management specifically, the Danish study was conducted when GLP-1 receptor agonists were approved only for type 2 diabetes in Denmark, so the findings reflect class-level psychiatric safety in a T2D population. Recent trial readouts in obesity (e.g., STEP UP semaglutide 7.2 mg, SYNCHRONIZE-1 survodutide, SURMOUNT-5 tirzepatide vs semaglutide, ATTAIN-MAINTAIN orforglipron maintenance) have not signaled new psychiatric concerns beyond the GLP-1 class background. Clinicians initiating GLP-1 RAs for obesity should still screen for and monitor mood symptoms per individual drug labels and FDA post-marketing surveillance updates.
Who was studied and how generalizable are the findings to obesity populations or to specific GLP-1 molecules?
The cohorts comprised Danish adults receiving GLP-1 receptor agonists for type 2 diabetes; one cohort compared 83,464 GLP-1 new users with 78,366 SGLT-2 inhibitor users, and the other compared 108,322 GLP-1 users with 55,411 DPP-4 inhibitor users. Follow-up extended through 31 December 2022. Findings may not generalize directly to obesity-only populations (where the indication, dose, and baseline psychiatric risk profile may differ), to specific molecules within the class (the analysis was at class level), or to settings outside the Danish health system. Obesity subgroup analysis was limited by underreporting of obesity in Danish registries.
What safety limitations and biases affected this analysis?
The authors noted possible exposure misclassification (adherence was inferred from prescription fills, not directly measured), residual confounding despite adjustment for sociodemographic and clinical factors, low event counts that limited precision, and competing risk of death that could lead to underestimation. Time-varying factors could still affect the self-controlled case-series analysis. Sensitivity analyses by recent psychiatric history and interaction testing by sex, age, and prior suicide attempts did not change the overall no-increase pattern, with one exception (an interaction involving prior attempts and sex in the SGLT-2 comparison). Triangulation across the two active-comparator cohorts and the within-person design strengthens the no-increased-risk inference.
How does this fit with FDA and EMA reviews and prior signals about GLP-1 RAs and psychiatric risk?
The FDA and EMA have previously reviewed post-marketing reports of suicidal ideation in patients receiving GLP-1 receptor agonists and concluded that the available evidence does not establish a causal association, while encouraging continued pharmacovigilance. This nationwide Danish analysis is broadly consistent with those regulatory reviews. Clinicians should continue to screen for depression and suicidal ideation in line with each drug's product label, particularly in patients with a personal or family history of psychiatric illness, and report concerning post-marketing signals through national pharmacovigilance channels.