Risk of Dementia in Patients With Type 2 Diabetes Using SGLT2 Inhibitors Versus DPP ‐4 Inhibitors: A Systematic Review and Meta‐Analysis

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a known risk factor for dementia, yet the cognitive impact of different glucose-lowering therapies remains unclear. Emerging evidence suggests sodium-glucose cotransporter-2 (SGLT2) inhibitors may confer neuroprotective benefits compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. OBJECTIVE: To compare the risk of incident dementia among patients with T2DM initiating SGLT2 inhibitors versus DPP-4 inhibitors. METHODS: A systematic search of PubMed, Scopus, and the Cochrane Central Register of Controlled Trials was conducted through June 1, 2025. The primary outcome was all-cause dementia. Secondary outcomes included Alzheimer's disease and vascular dementia. Random-effects models were used to pool adjusted hazard ratios (HRs), and subgroup analyses explored heterogeneity by age, sex, and specific SGLT2 agents. RESULTS: Nine retrospective cohort studies encompassing 2,433,086 individuals (601,692 SGLT2i users; 1,831,394 DPP-4i users) met inclusion criteria. SGLT2 inhibitors were associated with a significantly lower risk of all-cause dementia (HR = 0.74; 95% CI: 0.62-0.87), Alzheimer's disease (HR = 0.62; 95% CI: 0.52-0.74), and vascular dementia (HR = 0.54; 95% CI: 0.49-0.60) compared to DPP-4 inhibitors. Subgroup findings were largely consistent across age and sex. Dapagliflozin and empagliflozin showed significant benefit, while canagliflozin did not. CONCLUSION: Use of SGLT2 inhibitors is significantly associated with lower dementia risk compared to DPP-4 inhibitors in patients with T2DM. Prospective trials are warranted to confirm these findings and explore underlying mechanisms.