SGLT2 inhibitors versus GLP-1 receptor agonists and risk of kidney replacement therapy and healthcare utilization in bipolar disorder with chronic kidney disease: An active-comparator, new-user cohort study

Abstract

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 active-comparator, new-user 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 stages 1-3 initiating SGLT2i versus GLP-1 RA. Electronic health record data from the TriNetX network (2014–July 2026) identified eligible adults with documented treatment prescriptions; 3,971 SGLT2i and 5,608 GLP-1 RA users were identified, with 1:1 propensity score matching (PSM) yielding 2,557 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 2,557 SGLT2i users and 181 of 2,557 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 2,557 SGLT2i users and 965 of 2,557 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.