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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
PubMed
Abstract

Insights

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) showed a modestly lower risk for depression in older adults with type 2 diabetes compared to DPP4is, but not SGLT2is. This finding contributes to understanding GLP-1RA effects in managing T2D and mental health.

Area of Science:

  • Endocrinology
  • Geriatrics
  • Psychiatry

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show potential antidepressant effects, but population studies have yielded inconsistent results.
  • Type 2 diabetes (T2D) is common in older adults, and depression is a significant comorbidity.

Purpose of the Study:

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

Main Methods:

  • A target trial emulation study using U.S. National Medicare administrative data (2014-2020).
  • Older adults (≥66 years) with T2D initiating GLP-1RAs were matched 1:1 on propensity score with those initiating SGLT2is or DPP4is.
  • Cox proportional hazards regression models were used to estimate the hazard ratio (HR) for incident depression.

Main Results:

  • In GLP-1RA vs. SGLT2i comparison (14,665 pairs), no significant difference in depression risk was observed (HR: 1.07; 95% CI, 0.98-1.18).
  • In GLP-1RA vs. DPP4i comparison (13,711 pairs), GLP-1RA use was associated with a modestly lower risk for depression (HR: 0.90; 95% CI, 0.82-0.98).
  • The incidence of depression was relatively low in this cohort.

Conclusions:

  • Among older adults with T2D, GLP-1RA use was associated with a modestly lower risk of depression compared to DPP4is, but not SGLT2is.
  • Limitations include potential unmeasured confounders and limited generalizability to younger populations or those without T2D.

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