Individuals with bipolar disorder (BD) face elevated rates of chronic kidney disease (CKD) and premature mortality yet remain underrepresented in cardiorenal trials. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have established renoprotective benefits in the general population, their comparative effectiveness in BD with comorbid CKD is unknown. This observational cohort study examined risks of kidney replacement therapy (KRT) and healthcare utilization (HCU) (inpatient hospitalization and emergency department visits) among adults with BD and CKD Stage ≤3 initiating SGLT2i versus GLP-1 RA. Electronic health record data from the TriNetX network (2014-July 2026) identified eligible adults with documented treatment prescriptions; 3971 SGLT2i and 5608 GLP-1 RA users were identified, with 1:1 propensity score matching (PSM) yielding 2557 patients per arm. Cox proportional hazards regression generated adjusted hazard ratios (aHR) in the full cohort; Kaplan-Meier analyses were conducted in the matched cohort. In full cohort, SGLT2i use was associated with non-significantly lower KRT risk (aHR 0.87, 95% CI 0.71-1.06) and slightly higher HCU risk (aHR 1.18, 95% CI 1.10-1.28) relative to GLP-1 RA. In the matched cohort, 132 of 2557 SGLT2i users and 181 of 2557 GLP-1 RA users experienced KRT, with a borderline, non-significant difference favoring SGLT2i (86.88% vs. 83.48%; p = 0.06). For HCU, 990 of 2557 SGLT2i users and 965 of 2557 GLP-1 RA users experienced the outcome; 5-year HCU-free survival was slightly higher for SGLT2i users than GLP-1 RA users (36.42% vs. 33.27%; p = 0.004), reflecting convergence and late crossover of the Kaplan-Meier curves despite SGLT2i's higher hazard over most of the follow-up period. Residual confounding cannot be excluded, and competing mortality risk may have attenuated the observed hospitalization difference. Among patients with BD and CKD, SGLT2i use showed a non-significant trend toward lower KRT risk but was associated with significantly higher healthcare utilization compared with GLP-1 RA in the full cohort. Confirmation in prospective registries, large longitudinal studies, and randomized trials is needed.
