OBJECTIVE: To evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on dementia risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) among older adults with type 2 diabetes (T2D).
DESIGN: Retrospective cohort study using an active-comparator, new-user design with propensity score matching.
SETTING AND PARTICIPANTS: Data were obtained from the TriNetX Global Collaborative Network, which includes electronic health records from 134 health care organizations worldwide. Participants were adults aged ā„65 years with T2D who initiated GLP-1RA or DPP-4i therapy between January 2017 and November 2024.
METHODS: Eligible participants were matched 1:1 on baseline characteristics using propensity score matching (PSM). The primary outcome was incident dementia. Secondary outcomes included prescriptions for dementia-related drugs, Alzheimer's disease, and vascular dementia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were performed.
RESULTS: After PSM, 82,689 patients were included in each treatment group. GLP-1RA use was associated with a lower risk of dementia compared with DPP-4i (HR, 0.58; 95% CI, 0.55-0.61; P < .0001). Stratified analyses revealed consistent risk reductions across age, sex, and GLP-1RA type. In addition, GLP-1RA was also associated with lower risks of dementia-related drug prescriptions (HR, 0.76; 95% CI, 0.70-0.81), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.70), and vascular dementia (HR, 0.62; 95% CI, 0.55-0.70). Sensitivity analyses supported the robustness of these findings.
CONCLUSIONS AND IMPLICATIONS: GLP-1RA use in older adults with T2D is associated with a significantly lower risk of dementia compared with DPP-4i. These findings suggest the potential neuroprotective benefits of GLP-1RAs and highlight their importance in managing T2D with a view toward reducing dementia risk. Further studies are warranted to explore the underlying mechanisms and validate these observations in randomized controlled trials.
