2026 ECNP Congress

EP01-1044

Glucagon-like peptide-1 receptor agonists and risk of dementia: a nationwide new-user active-comparator study

Christoffer Stanislaus — M. Winther-Jensen, S. Stanislaus, M. Osler, K. Coello, M. Vinberg · Mental Health Centre North Zealand, The Early Multimodular Prevention and Intervention Research Institution EMPIRI, Hilleroed, Denmark

2026 ECNP Congress

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used in the management of type 2 diabetes mellitus (T2DM), a condition associated with accelerated cognitive decline and elevated dementia risk [1]. GLP-1 RAs improve glycemic control, promote cardiovascular and renal protection. Experimental studies suggest that GLP-1 signaling may exert neuroprotective effects by reducing neuroinflammation and oxidative stress and preserving synaptic plasticity. Early clinical studies of incretin-based therapies reported modest improvements in global cognition among patients with T2DM, with higher pooled Mini-Mental State Examination scores compared with other glucose-lowering drugs [2].

However, a systematic review and meta-analysis highlighted that the clinical evidence for GLP-1 RAs is limited and heterogeneous, including findings from a large nested case-control study showing lower odds of dementia with GLP-1 RA use, and a randomized trial showing no significant cognitive effects, leading to the conclusion that there is insufficient evidence to support a positive effect of incretin-based therapies [3].

Observational studies and secondary analyses suggest potential cognitive benefits of incretin-based therapies; however, findings are inconsistent, and evidence for GLP-1 RAs remains limited. It therefore remains unclear whether GLP-1 RA use influences dementia risk. We hypothesize that GLP-1 RA use is associated with a reduced risk of incident dementia compared with other glucose-lowering therapies.

Aims

To investigate whether use of GLP-1 receptor agonists is associated with a reduced risk of incident all-cause dementia compared with other glucose-lowering therapies in Danish adults, and to examine associations with cognitive decline over time in a nested subsample from the Danish Aging and Cognition (DanACo) cohort.

Methods

We will conduct a nationwide, register-based new-user, active-comparator cohort study including adults aged ≥18 years initiating GLP-1 RAs, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sodium–glucose cotransporter-2 (SGLT-2) inhibitors between 2014 and 2025. Individuals will be identified through Danish national health registers and followed from treatment initiation.

The primary outcome is incident all-cause dementia, defined as the first hospital diagnosis recorded in the National Patient Register or first redemption of dementia-specific medication.

Primary analyses will include intention-to-treat and as-treated approaches. We will use Cox proportional hazards regression to estimate hazard ratios (HRs) for risk of dementia in GLP-1 RA users vs SGLT-2 inhibitor users or DPP-4 inhibitor users, adjusting for age, sex, cardiovascular disease, hypertension, psychiatric history, and education.

A nested subsample from the Danish Aging and Cognition (DanACo) cohort will be used for cognitive phenotyping. In this subset, we will assess associations between GLP-1 RA exposure and change in standardized cognitive test scores over time, adjusting for baseline cognition, education, and lifestyle factors.

Results

Data extraction and statistical analyses are ongoing, and results will be available for presentation at the congress.

Conclusions

This study is expected to provide evidence on whether GLP-1 RAs are associated with a reduced risk of dementia and slower cognitive decline, with implications for clinical practice and future strategies for dementia prevention.

References

  1. Tang H, Donahoo WT, DeKosky ST, Lee YA, Kotecha P, Svensson M, et al. GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. JAMA Neurol. 2025;82(5):439-49.
  2. Chai S, Liu F, Yu S, Yang Z, Sun F. Cognitive protection of incretin-based therapies in patients with type 2 diabetes mellitus: A systematic review and meta-analysis based on clinical studies. J Diabetes Investig. 2023;14(7):864-73.
  3. Jin Y, Zhao H, Hou Y, Song G. The effects of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists on cognitive functions in adults with type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol. 2020;57(10):1129-44.