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.
In patients with bipolar disorder and chronic kidney disease, SGLT2 inhibitors may show a non-significant trend toward lower kidney replacement therapy risk but are associated with higher healthcare utilization compared to GLP-1 receptor agonists.
Where it sits
this study against the rest of the liraglutide corpusSummary and findings
This study compared the risks of kidney replacement therapy (KRT) and healthcare utilization (HCU) between adults with bipolar disorder and chronic kidney disease (CKD) using SGLT2 inhibitors versus GLP-1 receptor agonists. The study involved 3971 SGLT2i users and 5608 GLP-1 RA users, with a matched cohort of 2557 patients per arm. Findings indicated a non-significant trend toward lower KRT risk for SGLT2i users and higher HCU risk compared to GLP-1 RA users.
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; 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.
Background
This paper addresses the comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists in patients with bipolar disorder and chronic kidney disease. Prior studies have established the renoprotective benefits of these drug classes in the general population, but their effects in patients with bipolar disorder and comorbid chronic kidney disease remain unclear. Understanding these effects is crucial given the elevated rates of chronic kidney disease and premature mortality in this population.
Methods
This active-comparator, new-user cohort study utilized electronic health record data from the TriNetX network between 2014 and July 2026. The study identified adults with bipolar disorder and CKD stages 1-3 who initiated treatment with either SGLT2 inhibitors or GLP-1 receptor agonists. A total of 3971 SGLT2i and 5608 GLP-1 RA users were identified, with 2557 patients per arm matched using propensity score matching.
Results
In the full cohort, SGLT2i use was associated with an adjusted hazard ratio (aHR) of 0.87 (95% CI 0.71-1.06) for kidney replacement therapy risk, indicating a non-significant lower risk compared to GLP-1 RA. Additionally, SGLT2i users had an aHR of 1.18 (95% CI 1.10-1.28) for healthcare utilization risk. In the matched cohort, 132 SGLT2i users and 181 GLP-1 RA users experienced KRT, with a borderline non-significant difference favoring SGLT2i (p=0.06). For healthcare utilization, 990 SGLT2i users and 965 GLP-1 RA users experienced the outcome, with a statistically significant difference in 5-year HCU-free survival (p=0.004).
Interpretation
The findings suggest a non-significant trend toward lower kidney replacement therapy risk with SGLT2i compared to GLP-1 RA, but the clinical significance of this finding is uncertain due to the overlapping confidence intervals. The higher healthcare utilization associated with SGLT2i may indicate a need for further investigation into the long-term implications of these treatments in this population. Limitations such as residual confounding and competing mortality risk may affect the reliability of these results, necessitating confirmation through larger studies and randomized trials.
Key findings
- aHR 0.87, 95% CI 0.71-1.06 for KRT risk in full cohort
- aHR 1.18, 95% CI 1.10-1.28 for HCU risk in full cohort
- 132 of 2557 SGLT2i users and 181 of 2557 GLP-1 RA users experienced KRT in matched cohort
- 5-year HCU-free survival was 36.42% for SGLT2i users and 33.27% for GLP-1 RA users, p=0.004
- p=0.06 for KRT difference favoring SGLT2i in matched cohort
Limitations
- residual confounding cannot be excluded
- competing mortality risk may have attenuated hospitalization differences
- observational study design limits causal inference
- data sourced from electronic health records may have inaccuracies
- short follow-up period may not capture long-term outcomes