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

🥈 Top 2% JournalSep 15, 2025Alzheimer's & dementia : the journal of the Alzheimer's Association

GLP-1 receptor agonists and their link to dementia risk compared to other diabetes medicines in a large group of type 2 diabetes patients

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Abstract

In a cohort of diabetes patients aged ≥ 60 years, GLP-1 receptor agonists (GLP-1RAs) are associated with a 0.016 lower risk of dementia diagnosis compared to sulfonylureas.

Sustained exposure to GLP-1RAs does not significantly differ in dementia risk when compared to sodium-glucose cotransporter 2 inhibitors (SGLT2i).
GLP-1RAs are linked to a reduced risk of dementia diagnosis compared to dipeptidyl peptidase 4 inhibitors () with an adjusted risk difference of -0.013.
The findings suggest a modest risk reduction for dementia with GLP-1RAs versus DPP4i and sulfonylureas, but not versus SGLT2i.
The analysis utilized a rigorous causal inference approach based on clinical and claims data from multiple US health-care systems.

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INTRODUCTION: To address gaps in current research, this study aims to compare the impact of exposure to glucagon-like peptide-1 receptor agonists () versus sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (), and sulfonylureas () 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.

Key numbers

-0.013

Adjusted Risk Difference ( vs. )

Risk difference at 2.5 years with 95% confidence interval.

-0.016

Adjusted Risk Difference ( vs. )

Risk difference at 2.5 years with 95% confidence interval.

-0.001

Adjusted Risk Difference ( vs. )

Risk difference at 2.5 years with 95% confidence interval.

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Abstract

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