GLP-1 Receptor Agonists Reduce Dementia and Alzheimer Disease Risk in Patients with Diabetes and Advanced CKD: Real-World Evidence from TriNetX

Background: Patients with CKD and T2DM are at higher risk of dementia due to vascular dysfunction and chronic inflammation. GLP-1RAs have shown neuroprotective effects, but their impact in advanced CKD remains unclear. This study evaluated the association between GLP-1RA use and dementia risk in CKD stage 3b+ patients, compared to DPP4is. Methods: A retrospective cohort study was conducted using electronic health records from 67 U.S. healthcare organizations in the TriNetX network. Adults with CKD stage 3b+ and T2DM, newly prescribed GLP-1RAs or DPP4is between 2015–2020, were included. Patients with prior exposure, recent dementia diagnosis, or hospitalization were excluded. Outcomes included incident dementia, Alzheimer’s disease, vascular and frontotemporal dementia, Parkinson’s disease, movement disorders, and dementia with Lewy bodies. Follow-up was 90 days to 5 years. Analyses used Kaplan–Meier curves and Cox models. Results: GLP-1RA use was associated with lower risk of dementia (HR 0.80, 95% CI 0.71–0.91) and Alzheimer’s disease (HR 0.76, 95% CI 0.59–0.98) compared to DPP4is. Other outcomes showed no significant differences. Conclusion: GLP-1RAs may reduce dementia and Alzheimer’s disease risk in advanced CKD, supporting potential neuroprotective effects beyond glycemic control. Funding: Government Support – Non-U.S.Neurodegenerative Outcomes Comparison from GLP-1RAs and DPP4is - Clinical Outcomes GLP-1RAs (n = 12,351) DDP4is (n = 12,351) GLP-1RAs vs. DDP4is Dementia 455 (3.7) 562 (4.6) 0.80 (0.71–0.91) (p=0.001) Alzheimer 109 (0.9) 142 (1.1) 0.76 (0.59–0.98) (p=0.033) Vascular dementia 173 (1.4) 182 (1.5) 0.95 (0.77–1.16) (p=0.591) Frontotemporal dementia 10 (0.1) 14 (0.1) 0.64 (0.28–1.48) (p=0.294) Dementia with Lewy bodies 11 (0.1) 15 (0.1) 0.74 (0.34–1.61) (p=0.443) Parkinson 178 (1.4) 177 (1.4) 1.00 (0.81–1.23) (p=0.992) Extrapyramidal and movement disorders 1,057 (8.6) 994 (8.0) 1.06 (0.97–1.16) (p=0.178)