Abstract Disclosure: H. Park: None. S. Park: None. H. Kim: None. D. Byun: None. Subjects with type 2 diabetes (T2D) are at higher risk of developing cerebrovascular disease, cognitive decline, and dementia. Hyperinsulinemia and insulin resistance in the brain have been linked to amyloid beta metabolism, raising the risk of Alzheimer's dementia. Recently, several clinical studies have shown potential beneficial effects of sodium glucose co-transporter-2 (SGLT2) inhibitors, and thiazolidinediones, in the risk of cerebrovascular events and dementia in T2D. This study was aimed to investigate the comparative efficacy of SGLT2 inhibitors and thiazolidinediones in modifying the risk of cerebrovascular events, dementia, and Alzheimer's dementia. Using the common data model, we analyzed patients from December 31, 2011 to December 30, 2022 from 15 hospitals in South Korea. Clinical outcomes between SGLT2 inhibitors and thiazolidinediones were compared using hazard ratios (HRs), with large-scale propensity score matching and a random-effects model applied. Our analyses showed that subjects on SGLT2 inhibitors had a significantly reduced rate of cerebrovascular events (HR 0.2787, 95% CI 0.1882-0.4127, p<0.00001), dementia (HR 0.5395, 95% CI 0.3824-0.7614, p=0.0004), and Alzheimer's dementia (HR 0.586, 95% CI 0.4634-0.7411, p<0.00001), compared to those on thiazolidinediones. In summary, these results suggest that SGLT2 inhibitor administration is associated with a lower risk of cerebrovascular events, dementia, and Alzheimer's dementia compared to thiazolidinedione in subjects with T2D. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms. Presentation: 6/3/2024