Distinct temporal neuropsychiatric outcomes associated with GLP-1 receptor agonists versus SGLT2 inhibitors after acute kidney disease in type 2 diabetes

Background Neurological and neuropsychiatric complications may persist after acute kidney disease (AKD), particularly among patients with type 2 diabetes mellitus (T2DM). Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) provide established cardiorenal benefits, their associations with neurological outcomes after AKD remain uncertain. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and dialysis-requiring AKD receiving GLP-1RAs or SGLT2is were identified and balanced using 1:1 propensity score matching, yielding 3,398 patients in each group. Incident delirium and other neuropsychiatric outcomes were evaluated. The 90–365-day period was the primary analysis, with 90–180- and 90–720-day windows used to assess temporal patterns. Kaplan–Meier and multivariable Cox regression analyses were performed. Results During 90–365 days, GLP-1RA use was associated with better delirium-free survival than SGLT2i use (118/3,032 vs. 155/2,982 events; log-rank P = 0.009). This association remained significant after multivariable adjustment (adjusted hazard ratio [HR], 0.668; 95% CI, 0.488–0.914; P = 0.012). Statin use was independently associated with lower delirium risk (adjusted HR, 0.674; 95% CI, 0.492–0.924; P = 0.014), while exploratory analyses suggested a distinct association between LDL cholesterol of 100–129.9 mg/dL and delirium risk. In contrast, SGLT2i use showed a favorable association with depression during early follow-up, which attenuated over time. The GLP-1RA–delirium association was also attenuated by 90–720 days. Exploratory sensitivity analyses using non-overlapping follow-up intervals showed outcome-specific associations: adjusted differences in delirium were not significant, whereas depression and overall neurological complications were more frequent with GLP-1RA than with SGLT2i. Conclusions Among patients with dialysis-requiring AKD and T2DM, GLP-1RA and SGLT2i use showed outcome-specific associations with subsequent neuropsychiatric events. Although the primary analysis suggested a lower delirium risk with GLP-1RA, this association was not consistently observed in adjusted time-stratified analyses. These findings should be considered exploratory and require prospective validation.