Researchers have identified that glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which are widely used to control type 2 diabetes and obesity, present with an increased risk of developing depression than sodium-glucose cotransporter-2 inhibitors (SGLT2is). The research identified a 9% relative increase in depression risk and 2.2% absolute risk difference in GLP-1 RA users one year following treatment initiation. The researchers also noted a 26% decrease in all-cause mortality among GLP-1 RA users versus SGLT2i users. The study was published in the journal of Diabetes, Obesity & Metabolism by Yu Chang and colleagues.
This active-comparator, new-user cohort study utilized data from a deidentified electronic health record network between January 2016 and July 2024. Authors identified 51,408 adults with newly diagnosed type 2 diabetes and overweight or obesity who initiated treatment with either GLP-1 RAs (25,704 users) or SGLT2 inhibitors (25,704 users) following 1:1 propensity score matching to adjust for differences at baseline. Exclusion included patients with a history of mood disorders or antidepressant use. The main outcome was a composite of new depression diagnosis or antidepressant prescription between 1 month and 1 year after receiving treatment. Analyses used Cox proportional hazards models and time-varying models to evaluate risk over time.
Results
• Of the 51,408 patients (mean age 56.8 years, 48.9% male), GLP-1 RA exposure was linked to increased incidence of depression versus SGLT2 inhibitor exposure (17.0% vs. 14.8%).
• The hazard ratio (HR) for new-onset depression was 1.09 (95% CI, 1.04–1.14; p < 0.001), reflecting a 2.2% absolute risk difference.
• The risk was significantly greater in individuals older than 65 years (HR 1.15) and seemed to peak at 6 months before leveling off. In spite of the enhanced risk of depression, secondary analysis revealed that users of GLP-1 RAs had a reduced all-cause mortality (HR 0.74; 95% CI, 0.63–0.88), indicating a significant survival benefit.
The research showed that GLP-1 receptor agonist initiation was related to a low but statistically significant risk increase for depression compared with use of SGLT2 inhibitors mainly in older individuals and in the initial six months of therapy. These results indicate that although GLP-1 RAs continue to be extremely valuable for metabolic and survival benefits, greater mental health surveillance and educated patient conversations are needed to maximize long-term care.
Reference:
Chang, Y., Hsieh, M.-H., Ju, P.-C., & Chang, C.-C. (2025). Risk of depression with GLP-1 receptor agonists use in overweight or obese adults with type 2 diabetes: A new-user, active-comparator cohort study. Diabetes, Obesity & Metabolism, dom.70175. https://doi.org/10.1111/dom.70175
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