Sodium‐glucose cotransporter‐2 inhibitors and subtype‐specific dementia risk: A multinational and multiethnic cohort study

Abstract Aims Type 2 diabetes mellitus (T2DM) significantly increases the risk of dementia, including Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia. Although sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) have shown potential neuroprotective effects, previous studies were limited by small sample sizes, single‐country datasets and a lack of detailed analyses of dementia subtypes. Materials and Methods This retrospective cohort study utilized the TriNetX database, comprising de‐identified electronic health records from over 100 million patients across 98 healthcare organizations worldwide. Adults with T2DM initiating treatment with either SGLT2i or dipeptidyl peptidase‐4 inhibitors (DPP4i) between November 20, 2004, and November 20, 2024, were included. Propensity score matching (PSM) at a 1:1 ratio ensured balanced baseline characteristics. Primary outcomes included overall dementia and specific dementia subtypes (VaD, AD, other dementias), while secondary outcomes included all‐cause mortality. Results After 1:1 propensity score matching, 278 689 patients per group were analysed. SGLT2i use was associated with a lower incidence of overall dementia (2.9% vs. 6.7%; adjusted hazard ratio [AHR] 0.77, 95% confidence interval [CI], 0.75–0.79) and a lower risk of vascular dementia (AHR 0.80), Alzheimer's disease (AHR 0.82) and other dementias (AHR 0.68). These associations remained consistent across age, sex, baseline glycaemic control and concurrent medication use in subgroup analyses. SGLT2i use was also linked to lower all‐cause mortality (4.1% vs. 11.2%; AHR 0.66, 95% CI, 0.65–0.68). Findings were robust across sensitivity and subgroup analyses, supporting the potential neuroprotective effects of SGLT2i. Conclusions This large‐scale observational study suggests that SGLT2i use is associated with lower risks of multiple dementia subtypes and all‐cause mortality in patients with T2DM.