Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: A five-year retrospective cohort analysis of 160,752 patients

Abstract

Objectives: This study investigated the neuroprotective effects of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in reducing dementia risk among older adults with type 2 diabetes mellitus (T2DM), compared to dipeptidyl peptidase-4 inhibitors (DPP4i).

Methods: Using the TriNetX electronic health records network, we conducted a retrospective cohort study including adults aged ≥65 years with T2DM who initiated SGLT2i or DPP4i between January 1, 2013, and November 30, 2024. Propensity score matching was employed to create two balanced cohorts, with the primary outcome being new-onset dementia. Secondary outcomes included dementia-related drug use and subtypes of dementia, such as Alzheimer's disease and vascular dementia.

Results: After propensity score matching, 80,376 patients were included in each group. SGLT2i use was associated with a significantly lower risk of developing dementia compared to DPP4i (hazard ratio [HR], 0.54; 95 % confidence interval [CI]: 0.51-0.57; p < 0.001). Similar reductions were observed for dementia-related drug use (HR, 0.69; 95 % CI: 0.64-0.74; p < 0.001), Alzheimer's disease (HR, 0.53; 95 % CI: 0.48-0.60; p < 0.001), and vascular dementia (HR, 0.52; 95 % CI: 0.46-0.58; p < 0.001). Subgroup analyses showed consistent protective effects.

Conclusion: Compared to DPP-4i, SGLT2i use is associated with a lower risk of dementia in older adults with T2DM, with consistent benefits observed across diverse populations and patient subgroups. These findings highlight the potential of SGLT2i as a preventive strategy for cognitive decline and support further investigation in randomized controlled trials.

Keywords: Alzheimer’s disease; Dementia; Neuroprotection; SGLT2 inhibitors; Type 2 diabetes mellitus; Vascular dementia.