Efficacy and Safety of Dapagliflozin in Patients with CKD Stages 4-5

Background: Importance: Dapagliflozin improves renal outcome in patients with chronic kidney disease (CKD), but the effect of late initiating dapagliflozin when estimated glomerular filtration rate (eGFR) <25 mL/min/1.73m2 remains uncertain. Objective: To evaluate the efficacy and safety of dapagliflozin in patients with CKD stage 4 and 5. Methods: Design: Dapagliflozin and Renal Surrogate Outcomes in Advanced Chronic Kidney Disease (DAPA advKD) trial (NCT05196347) was an investigator-led, randomized, open-label, trial designed to recruit 180 patients with eGFR 10-30 mL/min/1.73m2 and eGFR decline ≥2.5 mL/min/1.73m2/yr. Interventions: Patients were randomized 2:1 to dapagliflozin (5-10 mg/d) + integrated CKD care or integrated CKD care alone. Main outcomes: The primary outcome was a preservation of eGFR decline ≥0.75 ml/min/1.73m2/yr. The 1st secondary outcome (renal endpoint) was a composite of renal replacement therapy, eGFR <5 mL/min/1.73m2, renal or cardiovascular (CV) death, or a >50% decline in eGFR. The 2nd secondary outcome (renal and CV endpoint) was a composite of renal outcome as above, acute kidney injury (AKI) and heart failure. Predefined safety outcomes were measured. Results: Over a median of 1.62 years, total eGFR slope (mL/min/1.73m2/yr) were -2.24 (-4.70 to -0.62) and -3.67 (-7.16 to -1.25) in the dapagliflozin and control groups, respectively; the primary outcome of eGFR slope difference was 1.06 (0.10 to 2.32) (p=0.019, linear mixed model). The secondary (renal) outcome occurred in 24/120 (20%) and 21/60 (35%) participants in the dapagliflozin and control groups, respectively (hazard ratio, 0.50 (0.28 to 0.89), p=0.019). The secondary (renal and CV) outcome occurred in 25/120 (21%) and 21/60 (35.0%) participants in the dapagliflozin and control groups, respectively (hazard ratio, 0.52 (0.29 to 0.93), p=0.028). There were higher incidence of AKI and heart failure in the control group, but higher incidence of eGFR dip in the dapagliflozin group. There was no difference of 5p- major adverse CV event and electrolyte imbalance. Conclusion: Among patients with eGFR 10-30 mL/min/1.73m2, the risks of eGFR decline and composite renal outcomes were lower with dapagliflozin than with control group. Funding: Other NIH Support - KMUH Hospital Grant, Commercial Support - AstraZeneca,