GLP-1RA comparative effectiveness against dementia onset relative to other antidiabetic medications in a large, multi-site cohort of patients with type 2 diabetes

Document Type

Article

Publication Date

9-1-2025

Publication Title

Alzheimers Dement

Abstract

INTRODUCTION: To address gaps in current research, this study aims to compare the impact of exposure to glucagon-like peptide-1 receptor agonists (GLP-1RA) versus sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), and sulfonylureas (SU) on reducing the risk of dementia, using a rigorous targeted learning causal inference approach.

METHODS: Using clinical and claims data from four diverse US health-care systems, we emulated three two-arm trials contrasting sustained treatment with GLP-1RA versus SGLT2i, DPP4i, and SU on dementia diagnosis. We included diabetes patients aged ≥ 60 years who initiated medication between 2014 and 2022. We estimated cumulative risk differences at 2.5 years.

RESULTS: In Cohort 1, there was no evidence of differential dementia risk between sustained exposure to GLP1-RA versus SGLT2i (adjusted risk difference [aRD] -0.001, 95% confidence interval [CI] -0.004, 0.001). In Cohorts 2 and 3, GLP-1RA was associated with reduced risk of dementia diagnosis compared to DPP4i and SU, respectively (aRD -0.013, 95% CI -0.017, -0.009; aRD -0.016, 95% CI -0.018, -0.015).

DISCUSSION: Rigorous causal inference analysis suggests that sustained exposure to GLP-1RA may modestly reduce risk of dementia, compared to DPP4i or SU exposure-but not compared to SGLT2i.

HIGHLIGHTS: We researched the comparative effects of diabetes medications on dementia. We studied a large, diverse observational cohort of patients with diabetes in the United States. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may modestly reduce risk of dementia compared to dipeptidyl peptidase 4 inhibitor or sulfonylurea exposure. GLP-1RAs do not show evidence of dementia risk reduction compared to sodium-glucose cotransporter 2 inhibitors. Physicians may consider this when making prescription decisions with patients.

Medical Subject Headings

Aged; Female; Humans; Male; Middle Aged; Cohort Studies; Dementia/prevention & control/epidemiology; Diabetes Mellitus; Type 2/drug therapy/complications; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use; Glucagon-Like Peptide-1 Receptor Agonists; Hypoglycemic Agents/therapeutic use; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use; Sulfonylurea Compounds/therapeutic use; United States; Retrospective Studies; causal inference; diabetes; diabetes medications; glucagon‐like peptide‐1 receptor agonist; longitudinal data; targeted learning

PubMed ID

40952016

Volume

21

Issue

9

First Page

70621

Last Page

70621

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