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Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes : A Target

Huilin Tang¹, Ying Lu¹, William T Donahoo²

¹Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida (H.T., Y.L.).

Annals of Internal Medicine

|February 24, 2025

Abstract

Background:

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results.

Objective:

To compare the risk for depression in older adults with type 2 diabetes (T2D) initiating treatment with GLP-1RAs versus sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is).

Design:

Target trial emulation study.

Setting:

U.S. National Medicare administrative data from January 2014 to December 2020.

Patients:

Adults aged 66 years or older with T2D initiating treatment with a GLP-1RA were matched 1:1 on propensity score with those initiating treatment with either an SGLT2i or a DPP4i.

Measurements:

The primary end point was incident depression. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% CI within matched groups.

Results:

A total of 14 665 matched pairs of older adults were included in the cohort for GLP-1RAs versus SGLT2is; the rate difference of depression between GLP-1RA users and SGLT2i users was 3.48 (95% CI, -0.81 to 7.78) per 1000 person-years, with an HR of 1.07 (CI, 0.98 to 1.18). In the cohort for GLP-1RAs versus DPP4is (13 711 matched pairs), the rate difference was -5.78 (CI, -10.49 to -1.07) per 1000 person-years, with an HR of 0.90 (CI, 0.82 to 0.98).

Limitation:

Unmeasured confounders (such as hemoglobin A_1c levels and body mass index), outcome misclassification, and limited generalizability to all GLP-1RA users (for example, younger populations or those without T2D receiving the drug for obesity treatment).

Conclusion:

Among older adults with T2D, the incidence of depression was relatively low. Use of GLP-1RAs was associated with a modestly lower risk for depression compared with use of DPP4is, but not SGLT2is.

Primary Funding Source:

National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

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