Comparative effectiveness of SGLT-2 inhibitors and GLP-1 receptor agonists on the risk of incident dementia after acute kidney injury: a target-trial emulation.

Patients with type 2 diabetic mellitus (T2DM) who recover from acute kidney injury (AKI) face substantial risks of cognitive decline and kidney disease progression. Whether sodium-glucosecotransporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) differentially affect incident dementia in this setting is uncertain. We conducted a target trial emulation using TriNetX electronic health records (2015-2024). Adults with T2DM hospitalized for AKI requiring emergent dialysis (AKI-D) were indexed 90 days post-discharge and classified as users of SGLT2i or GLP-1 RAs within that window (intention-to-treat). One-to-one (1:1) propensity score matching (PSM) was performed to control for potential confounding factors. The primary outcome was incident degenerative and vascular dementia. The prespecified secondary outcomes included all-cause mortality, kidney events, and major adverse cardiovascular events (MACE). Among 14,460 eligible patients, SGLT2i users showed a lower risk of degenerative dementia (2.8% vs. 3.9%, aHR 0.78, 95% CI 0.63-0.97; p = 0.028; E value 2.58) and adverse kidney events (7.2% vs. 9.2%, aHR 0.82, 95% CI 0.71-0.95; p = 0.006; E value 2.15) than GLP-1 RAs users. No significant differences were observed for vascular dementia, mortality, or MACE. Safety profiles were similar, with fewer gastrointestinal adverse events in the SGLT2i group. In patients with T2DM recovering from AKI, SGLT2i therapy was associated with reduced risks of degenerative dementia and kidney disease progression compared with GLP-1 RAs. These results suggest that SGLT2i may be a favorable option for cognition during AKI recovery, though further prospective studies are needed to confirm these findings.