Sodium-Glucose Cotransporter-2 Inhibitor Therapy and Longitudinal Changes in Kidney Function among Veterans with Autosomal Dominant Polycystic Kidney Disease

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a pillar of kidney disease therapy, but their efficacy remains unknown in Autosomal Dominant Polycystic Kidney Disease (ADPKD). We evaluated effects of SGLT2i on kidney function in ADPKD. Methods: This retrospective cohort study within the Veterans Health Administration included adults with an ADPKD diagnosis code who initiated SGLT2i between January 2017 and May 2023. Repeated measures models were used to evaluate eGFR slope before and after SGLT2i initiation. Among patients with ADPKD and type 2 diabetes mellitus (T2DM), a target trial emulation was used to compare the effects of SGLT2i versus dipeptidyl peptidase-4 inhibition (DPP4i) on eGFR slope. Results: Among 348 eligible patients with ADPKD who started an SGLT2i, 93% were male, mean ± standard deviation age was 68 ± 11, and median eGFR was 53 (interquartile range: 16-127) ml/min/1.73m 2 . In adjusted analyses, the pre-initiation eGFR slope was -0.79 (95% confidence interval: -1.26, -0.33) ml/min/1.73m 2 per-90-days. The eGFR slope steepened to -2.78 (-4.04, -1.53) ml/min/1.73m 2 during the first three months post-initiation, and then stabilized to -0.07 (-0.72, 0.58) ml/min/1.73m 2 during months 3-to-12 post-initiation. The target trial emulation compared 217 SGLT2i-users with 198 DPP4i-users. In adjusted analyses, eGFR declined -4.03 (-6.45, -1.60) mL/min/1.73m 2 per-90-days faster in SGLT2i- versus DPP4i-users during the first three months post-initiation; however, during the subsequent 3-to-12 months, the slope was more stable in SGLT2i- than DPP4i-initiators, with a difference of 1.29 (0.16, 2.41) mL/min/1.73m 2 per-90-days. Conclusions: In older patients with mild ADPKD and a high prevalence of diabetes and cardiovascular disease who initiated an SGLT2i, there was an initial three-month decline in eGFR followed by stabilization during the remainder of the year-long follow-up. Compared with DPP4i use, SGLT2i use was associated with a slower eGFR decline between 3-to-12 months post-initiation in patients with concurrent T2DM. These findings suggest that SGLT2is are potentially beneficial in older individuals with ADPKD in whom comorbid disease may play a greater role in kidney function decline, but further studies are required.