Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with an increased risk of brain-related diseases such as Parkinson’s disease, dementia, and ischemic stroke. Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown protective effects against these conditions, but evidence in MASLD populations remains limited.

Aims: To compare the effects of SGLT2Is and GLP-1RAs with dipeptidyl peptidase-4 inhibitors (DPP-4Is) on the risk of brain-related outcomes in MASLD.

Methods: We conducted an active-comparator new-user cohort study using the Korean National Health Insurance Service database (2012-2023) among patients with MASLD excluding those with a prior history of Parkinson’s disease, dementia, or ischemic stroke. Two cohorts were established: one comparing SGLT2Is with DPP-4Is, and another comparing GLP-1RAs with DPP-4Is. Propensity score matching (1:1) was applied to balance covariates, and hazard ratios (HR) with 95% confidence interval (CI) were estimated using Cox proportional hazard models among matched populations.

Results: In the first cohort, 125,903 SGLT2Is users (mean age 52; male 72.1%) and 535,423 DPP4Is users (mean age 55.7, male 73.9%) were included before PS matching. In intention-to-treat analysis, SGLT2Is were associated with reduced risks of dementia (HR 0.69, 95% CI 0.64-0.74), and ischemic stroke (0.92, 0.85-0.99). There was no statistically significant reduction in Parkinson’s disease (0.83, 0.68-1.01). In the second cohort, 3,641 GLP-1RAs users (mean age 49; male 61.3%) and 672,253 DPP4Is users (mean age 55.7; male 73.1%) were included. GLP-1RAs had significantly reduced risks of dementia (0.64, 0.43-0.96), while no significant associations were observed for Parkinson’s disease (0.98, 0.37-2.60), or ischemic stroke (1.05, 0.67-1.67). As-treated analysis also supported these findings across all outcomes.

Conclusion: SGLT2Is or GLP-1RAs was associated with a lower risk of dementia. However, their effects on Parkinson’s disease and ischemic stroke were not statistically significant.