GLP-1 receptor agonists reduce dementia and Alzheimer disease risk in diabetic patients with CKD

BACKGROUND: Patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia and Alzheimer's disease due to vascular dysfunction, insulin resistance and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective properties; however, their impact on dementia risk in diabetic patients with CKD remains uncertain. This study evaluated the association between GLP-1RA use and dementia risk in patients with CKD stage 3 or later, compared with dipeptidyl peptidase-4 inhibitors (DPP4is). METHODS: This retrospective cohort study analyzed data from the TriNetX global research network, comprising electronic medical records from 67 healthcare organizations in the US Collaborative Network. We identified patients with CKD stage 3 or later and T2DM who were newly prescribed GLP-1RAs or DPP4is between 1 January 2015 and 31 December 2020. Patients with prior GLP-1RAs or DPP4i use, a dementia diagnosis within 12 months before the index date or recent hospitalization were excluded. The primary outcome was the incidence of dementia, Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, and dementia with Lewy bodies, assessed over a follow-up period ranging from 90 days to 5 years. Statistical analyses included Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: GLP-1RA use was associated with a significantly lower risk of dementia [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.71-0.91, P = .001] and Alzheimer's disease (HR 0.76, 95% CI 0.59-0.98, P = .033) compared with DPP4i use. However, no significant differences were observed in vascular dementia, frontotemporal dementia, Parkinson's disease, extrapyramidal and movement disorders, or dementia with Lewy bodies. CONCLUSIONS: GLP-1RA therapy may reduce the risk of dementia and Alzheimer's disease in patients with CKD stage 3 or later, offering potential neuroprotective benefits beyond glycemic control. Research is needed to confirm these findings and optimize treatment strategies for this vulnerable population.