Sodium-Glucose Cotransporter 2 Inhibitors for Lithium-Associated Kidney Dysfunction in Mood Disorders: A Real-World Historical Cohort Study

Introduction Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed for type 2 diabetes, have shown promise in improving renal outcomes in patients with and without diabetes. However, their effect on lithium-associated kidney dysfunction remains unknown. Methods This historical cohort study included patients from Mayo Clinic (2001-2023) with mood disorders who received lithium for ≥6 months and later used SGLT2i for ≥1 month. Data on SGLT2i use and lithium treatment were extracted from electronic health records. Serum creatinine values were used to calculate estimated glomerular filtration rate (eGFR) trajectories. Linear mixed-effects models with piecewise linear splines were used to estimate eGFR slopes before and after SGLT2i initiation, adjusted for age and sex. Results Fifty-six patients (mean age 57.4 years, 46.4% female), predominantly with bipolar disorder (86%), were included. The mean eGFR, measured nearest to SGLT2i initiation, was 77.9±26.0 mL/min/1.73 m 2 , and the mean duration of SGLT2i use was 19.5±17.8 months. Before SGLT2i initiation, eGFR declined at a rate of −1.43 mL/min/1.73 m 2 per year (p<0.001). After initiation, eGFR increased by 0.69 mL/min/1.73 m 2 per year, reflecting a +2.13 change (p=0.025). Sensitivity analyses, including only patients on lithium at SGLT2i initiation (n=22) or who had >1 year of SGLT2i use (n=29) showed similar, though non-significant, changes in slopes. Conclusion SGLT2i treatment was associated with a significant improvement in eGFR trajectory in patients with mood disorders who received long-term lithium therapy. These findings suggest a potential role for SGLT2is in mitigating lithium-associated kidney dysfunction and highlight the need for randomized controlled trials in this population.