TOPLINE:

Among patients with type 2 diabetes (T2D) and overweight or obesity, the initiation of GLP-1 receptor agonists (RAs) was associated with a 9% higher risk for incident depression than the initiation of SGLT2 inhibitors, with the association being stronger in older adults. The increased risk plateaued after 6 months and should be balanced against the mortality benefit associated with GLP-1 therapy.

METHODOLOGY:

• GLP-1 RAs have raised ongoing concerns about neuropsychiatric harms, particularly depression and suicidality, with conflicting evidence leaving clinicians uncertain how to counsel patients.
• To compare the risk for incident depression between GLP-1 RAs and SGLT2 inhibitors, researchers conducted a cohort study using deidentified electronic health records from healthcare organizations predominantly in the US from January 2016 to July 2024.
• They identified 25,704 new GLP-1 RA users (mean age, 56.7 years; 48.6% men) matched 1:1 with 25,704 SGLT2 inhibitor users; all patients had newly diagnosed T2D and overweight or obesity, and those with prior mood disorders were excluded.
• The primary outcome was a composite of incident depression diagnosis or initiation of antidepressants, assessed from 1 month to 1 year after the patient’s first recorded prescription of any glucose-lowering medication.

TAKEAWAY:

• The use of GLP-1 RAs vs SGLT2 inhibitors was associated with a 9% higher relative rate of incident depression (17.0% vs 14.8%; hazard ratio [HR], 1.09; 95% CI, 1.04-1.14); the association was more pronounced in adults aged 65 years or older (HR, 1.15; 95% CI, 1.08-1.24) and plateaued after approximately 6 months.
• Among individual agents, the association was statistically significant for liraglutide (HR, 1.17; 95% CI, 1.09-1.25) and semaglutide (HR, 1.07; 95% CI, 1.01-1.13) but not for tirzepatide.
• Furthermore, GLP-1 RA use was associated with an increased risk for both a new depression diagnosis (HR, 1.12; 95% CI, 1.05-1.20) and initiation of an antidepressant (HR, 1.07; 95% CI, 1.02-1.12).
• In secondary analysis, GLP-1 RA use was associated with a significantly lower risk for all-cause mortality (HR, 0.74; 95% CI, 0.63-0.88).

IN PRACTICE:

“This risk must be carefully balanced against the substantial mortality benefit afforded by GLP-1 RAs,” the authors of the study wrote.

SOURCE:

The study was led by Yu Chang, MD, Department of Psychiatry, Chung Shan Medical University Hospital in Taichung, Taiwan. It was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The reliance on administrative and diagnostic codes for outcome ascertainment may have introduced misclassification bias. The study’s focus on patients with overweight/obesity and T2D limited generalizability to other populations or patients with obesity alone. Because co-initiation of other glucose-lowering agents (eg, metformin) at the date of initiation of GLP-1 RAs or SGLT2 inhibitors was excluded, the findings may have limited applicability to typical combination therapy in real-world practice.

DISCLOSURES:

No information on funding sources was available. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.