GLP-1 RAs and Suicidality: Weighing Out The Risks

Abstract

Background: Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) are at the forefront of medical therapy for patients with obesity and type 2 diabetes mellitus. They are relatively new to the market, and have increased in popularity over the last few years because of their positive effects of glucose control and weight loss. In mid 2023, reports of suicidal behavior with use of GLP-1 RAs prompted the European Medicines Agency (EMA) to investigate further. Determining adverse effects of GLP-1 RAs is crucial because these medications are going to be around for the foreseeable future and continue to gain popularity. Suicide is one of the leading causes of death in the United States, and if there is an association of suicidality with GLP-1 RA use, it is important for clinicians to know when they are prescribing these medications.
Objectives: To evaluate the risk of suicidality in adult patients with obesity or type 2 diabetes mellitus who are taking GLP-1 RAs.
Design: Multi-study review
Methods: A search of the National Library of Medicine PubMed, Cochrane, and Embase was completed in December 2024 using the search terms “GLP-1 receptor agonist AND (depressi* OR suicid* OR mental health)” and yielded 246 results. The search was limited using filters such as “humans” and “within the last year”. Various inclusion and exclusion criteria were applied. 4 articles were analyzed for outcomes and validity assessments, and the level of evidence of each article was made.
Results: Study #1: The authors found an 106% increase risk for suicidal behavior in patients taking GLP-1 RAs. HR=2.06 overall. Level of evidence is of moderate quality. Study #2: The authors found that semaglutide did not increase risk of suicidal ideation or behavior compared to placebo. Level of evidence is of high quality. Study #3: The authors found that suicidal ideation or behavior risk is similar and not statistically significant when comparing GLP-1 RAs to SGLT-2 inhibitors and DPP4 inhibitors. Level of evidence is of moderate quality. Study #4: The authors found that the use of semaglutide is associated with a lower risk for incident and recurrent suicidal ideation. Level of evidence is of moderate quality.
Conclusion: The four studies all had a primary outcome of suicidality risk with GLP-1 RAs and showed mixed results. All studies are assumed to be of adequate power due to a large sample size, but all of the studies are limited by study design flaws because they are cohort studies. Further investigation is needed to determine an association between GLP-1 RA use and increased suicidality.