SGLT2 inhibitors versus DPP-4 inhibitors and dementia risk in type 2 diabetes: A meta-analysis of cohort studies

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown neuroprotective potential. This meta-analysis aimed to compare the effects of SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors on dementia risk in patients with type 2 diabetes mellitus (T2DM). METHODS: A systematic search of PubMed, EMBASE, Cochrane Library, and Web of Science was conducted from inception through May 2025. Cohort studies comparing dementia incidence in T2DM patients treated with SGLT2 inhibitors versus DPP-4 inhibitors were included. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Data were pooled using a random-effects model in STATA 12.0, with incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) calculated for dementia outcomes. RESULTS: Eight cohort studies (1275,257 participants) were analyzed. SGLT2 inhibitor use was associated with a 33 % lower risk of all-cause dementia compared to DPP-4 inhibitors (I² = 0.0 %, P = 0.816; IRR = 0.666; 95 % CI: 0.484-0.918; P < 0.05). Subgroup analyses indicated non-significant risk reductions for Alzheimer's disease (I² = 0.0 %, P = 0.994; IRR = 0.654; 95 % CI: 0.352-1.212; P = 0.177) and vascular dementia (I² = 0.0 %, P = 0.971; IRR = 0.573; 95 % CI: 0.204-1.605; P = 0.289). CONCLUSIONS: SGLT2 inhibitors are associated with a significantly reduced risk of all-cause dementia in T2DM patients compared to DPP-4 inhibitors. While trends favoring SGLT2 inhibitors were observed for dementia subtypes, further long-term studies are needed to confirm these associations.