New study confirms GLP-1 medications are safe for mental health in diabetes

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Mar 2 2025

A large-scale study analyzing data from over 60 million patients finds no evidence that GLP-1 receptor agonists increase suicidality risk in type 2 diabetes patients, challenging previous safety concerns.

Study: Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study. Image Credit: azimmytws / Shutterstock.com

A recent BMJ study determines whether the use of glucagon-like peptide-1 (GLP-1) receptor agonists by type 2 diabetes (T2D) patients increases the risk of self-harm, suicidal ideation, and suicide as compared to patients prescribed dipeptidyl peptidase-4 (DPP-4) or sodium-glucose cotransporter-2 (SGLT-2) inhibitors.

GLP-1 and the risk of suicidality

The GLP-1 receptor agonist drug class is widely prescribed to manage T2D. These medications are highly effective in achieving glycemic control while also promoting beneficial cardiorenal effects and reducing the risk of all-cause mortality.

After the Icelandic Medicines Agency published initial safety concerns in July 2023, regulatory bodies worldwide have launched investigations to assess the potential risk of suicidality among GLP-1 receptor agonist users. However, the lack of available evidence has limited researchers from making definitive conclusions on this potential association.

Several mechanisms may be involved in this potential association, some of which include sudden weight loss and hyperactivity of the hypothalamic-pituitary-adrenal axis. Nevertheless, the exact way by which the risk of suicidal ideation and self-harm may be increased by GLP-1 receptor agonist use remains unclear.

About the study

The current observational study estimates the average treatment effect of continuous GLP-1 receptor agonist use on suicidal ideation, self-harm, and suicide among T2D patients. Data from over 60 million patients treated in over 2,000 general practices were obtained from the United Kingdom Clinical Practice Research Datalink (CPRD) GOLD and Aurum.

Patients were classified into two cohorts. The first cohort comprised individuals who started and continued either a GLP-1 receptor agonist or DPP-4 inhibitor for the first time between January 1, 2007, and December 31, 2020. The second group included individuals who started and continued either a GLP-1 receptor agonist or SGLT-2 inhibitor for the first time between January 1, 2013, and December 31, 2020.

The primary outcome was suicidality, which was defined as a composite of hospital admission for self-harm, suicidal ideation, or completed suicide. Secondary outcomes included each of these events considered separately.

Study findings

The study cohort consisted of 36,082 and 234,028 GLP-1 receptor agonist and DPP-4 inhibitor users, respectively, who were followed for a median of 1.3 and 1.7 years. Comparatively, 32,336 GLP-1 receptor agonists and 96,212 SGLT-2 inhibitor users were followed for a median of 1.2 and 1.2 years, respectively.

GLP-1 receptor agonist users had higher levels of hemoglobin A_1c and longer duration of T2D. These individuals were also more likely to have a history of anxiety, depression, schizophrenia, self-harm, and insomnia.

The weighted incidence of suicidality was 3.9 and 3.7 for every 1,000 person-years among GLP-1 receptor agonist and DPP-4 inhibitor users, respectively. No significant differences in secondary outcomes were observed post-weighting, and all results were consistent across multiple sensitivity analyses.

Prior to the weighting of covariates, GLP-1 receptor agonist users were more likely to be obese, diagnosed with T2D for a longer duration, and female as compared to those prescribed SGLT-2 inhibitors. Patients using GLP-1 receptor agonists were also more likely to have microvascular complications and a history of depression.

The weighted incidence of suicidality was 4.3 and 4.6 for every 1,000 person-years in individuals prescribed GLP-1 receptor agonists and SGLT-2 inhibitors, respectively. No significant differences were noted in the secondary outcomes post-weighting between these two groups, with all results consistent across multiple sensitivity analyses.

Conclusions

The study findings indicate that the use of GLP-1 receptor agonists is not associated with an increased risk of self-harm, suicidal ideation, and suicide as compared to DPP-4 and SGLT-2 inhibitors among T2D patients.

The database utilized for the current study allowed the researchers to consider a wide range of confounding factors that are often absent in other administrative databases. Another key strength is the study design, which minimized biases related to the inclusion of prevalent users without excluding patients with a history of self-harm or suicidal ideation. This is particularly important, as individuals with a history of self-harm or suicidal ideation could be most vulnerable to adverse psychiatric events related to GLP-1 receptor agonist use.

A notable limitation of the current study is the potential presence of residual confounding. Exposure misclassification is also possible, as prescriptions in the database only included those written by general practitioners. Furthermore, the results of some secondary analyses should be interpreted with caution due to wide confidence intervals stemming from the rarity of the outcomes.