Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study
BMJ 2025; 388 doi: https://doi.org/10.1136/bmj-2024-080679 (Published 26 February 2025) Cite this as: BMJ 2025;388:e080679Linked Editorial
GLP-1 receptor agonists and suicidality
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Dear Editor
This study provides valuable insights into the association between GLP-1 receptor agonists (GLP-1 RAs) and the risk of suicidality in people with type 2 [1] diabetes. However, we have two concerns about the analytical approaches. The study does not account for the competing risk of death, which could impact the interpretation of outcomes. Competing risks are typically addressed through sensitivity analyses to assess the robustness of results [2]. Incorporating such an analysis would provide a more comprehensive evaluation of the true relationship between GLP-1 RAs and risk of suicidality. Furthermore, different GLP-1 RAs (e.g. Liraglutide and Semaglutide) may have distinct neurological effects. Future research should analyze the impact of individual GLP-1 RAs separately.
References
[1]. Shapiro SB, Yin H, Yu OHY, Rej S, Suissa S, Azoulay L. Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study. BMJ. 2025 Feb 26;388:e080679.
[2]. Austin PC, Lee DS, Fine JP. Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation. 2016 Feb 9;133(6):601-9.
Competing interests: NA
Xin Wen, MMed
Clinical Research Centre
Zhujiang Hospital of Southern Medical University
Guangzhou, China
Hongbo Guo, PhD
Department of Neurosurgery
Zhujiang Hospital of Southern Medical University
Guangzhou, China
Zhaohua Zhu, PhD
Department of Rheumatology, Royal North Shore Hospital and Sydney Musculoskeletal Health, Kolling Institute, University of Sydney, Sydney, Australia
Competing interests: No competing interests
Dear Editor,
Shapiro et al. 2024 [https://doi.org/10.1136/bmj-2024-080679] explore the association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality risk among patients with type 2 diabetes [1]. This study provided valuable insights into the safety profile of GLP-1 receptor agonists concerning suicidality in patients with type 2 diabetes. Nevertheless, a few critical aspects warrant scrutiny.
Firstly, despite the study’s robust methodology, residual confounding remains a concerning limitation. Although relevant adjustments were made for several variables, other unquantifiable factors, such as family history of psychiatric disorders and accessibility to mental health services, equally influence suicidality risk [1]. Social determinants of health play a vital role in mental health outcomes, despite these being partially explored in the study [2].
Secondly, the study population was restricted to individuals with type 2 diabetes, thus limiting the results' applicability to those using GLP-1 RAs for other disease management. GLP-1 RAs may have differential psychiatric effects in people without diabetes [3]. Therefore, further research should evaluate the effects in broader populations to enhance external validity.
Additionally, the study fails to explore the potential biological mechanisms linking GLP-1 RAs to suicidality risk. Recent studies show that GLP-1 receptors are expressed in the brain and could influence mood [4]. Neurobiological investigations would provide more information on the causal pathways.
Lastly, Shapiro et al. 2024 offer valuable insight into the safety of GLP-1 RAs concerning suicidality risk in type 2 diabetes. Nevertheless, gaps related to residual founding, generalizability, and mechanistic comprehension constrain the study’s conclusiveness. Addressing these gaps in future research will enhance our understanding of the psychiatric ramifications of GLP-1 RAs.
References
[1] Shapiro SB, Yin H, Yu OHY, Rej S, Suissa S, Azoulay L. Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study. BMJ. 2025 Feb 26;e080679.
[2] Chelak K, Chakole S. The role of social determinants of health in promoting health equality: A narrative review. Cureus [Internet]. 2023;15(1):1–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899154/
[3] Sasidhar Gunturu. The Potential Role of GLP-1 Agonists in Psychiatric Disorders: A Paradigm Shift in Mental Health Treatment. Indian Journal of Psychological Medicine. 2024 Apr 12;46(3):193–5.
[4] Kabahizi A, Wallace B, Lieu L, Chau D, Dong Y, Hwang E, et al. Glucagon‐like peptide‐1 (GLP‐1) signaling in the brain: From neural circuits and metabolism to therapeutics. British Journal of Pharmacology. 2021 Nov 4;179(4):600–24.
Competing interests: No competing interests
Re: Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study
Dear Editor
It was good to go through this article.
Especially covering this class of drug which is very much topical. Even though this class has been in the market for the last two decades, in recent years, due to its weight loss benefits it has garnered more popularity widely.
Going through the study, acts as a reminder to prescribing clinicians to keep the in mind the background mental health issues in patients.
Couple of points to keep in mind for studies of this nature
1. Background risk of underling physical comorbidities and mental health issues in the patients - would be helpful.
2. Screening of underlying MH illness / depression - would give more clarity.
3. Control group - if possible having a control group with comparable comorbidities will help to quantify any associated risk with this drug.
4. Follow up period - Having a longer follow up period would also help to shed light on possible reason for association with suicidibility - Is there any association with side affects contributing to this, are the cohort of patients enrolled were they at higher risk compared to the general public in regards to suicidability?
I would be keenly waiting for a prospective trial done on this class of drug to shed light on mental health symptoms.
Thanks
Competing interests: No competing interests