Mediators of the Kidney Protective Effects of Dapagliflozin in Patients with CKD with or Without Type 2 Diabetes

Background: The DAPA-CKD trial demonstrated that dapagliflozin attenuates progression of chronic kidney disease (CKD) in patients with and without type 2 diabetes. This post-hoc analysis assessed possible mediators of the observed kidney protective effect. Methods: In DAPA-CKD, 4304 patients with an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urine albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to receive dapagliflozin 10 mg or placebo. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or kidney or cardiovascular death. We considered biomarkers that were significantly affected by dapagliflozin versus placebo over time, as assessed using mixed effect model for repeated measures: UACR, hematocrit, HbA1c, blood pressure (systolic [SBP] and diastolic [DBP]), serum sodium and potassium, and body weight. We calculated the proportion of the effect of dapagliflozin explained by the change in each biomarker by fitting a multivariable-adjusted, time-dependent, Cox model, adjusted for baseline sex, age, body mass index, eGFR, SBP, and UACR. We estimated confidence intervals using 1000-iterations bootstrap. Analyses were repeated by type 2 diabetes status. Results: Compared with placebo, dapagliflozin reduced UACR (29.3% [95%CI: 25.2-33.1]), SBP (2.9mmHg [2.3-3.6]), DBP (1.0mmHg [0.6-1.4]), HbA1c (0.08% [0.03-0.14]), serum potassium (0.035mEq/L [0.012-0.057]) and body weight (0.85kg [0.61-1.08]), and increased hematocrit (2.3% [2.1-2.5]) and serum sodium (0.14mEq/L [0.02-0.26]). The effect of dapagliflozin on the primary outcome was explained by changes in hematocrit (35.5% [95%CI 24.3-69.0]), UACR (35.4% [23.0-52.8]), and SBP (4.9% [1.3-9.1]), but not through the other tested biomarkers. The proportion of dapagliflozin’s effect explained by change in hematocrit was 31.2% (20.0-70.3) in participants with type 2 diabetes, and 32.4% (14.3-76.5) in those without type 2 diabetes. The respective proportions explained by the change in UACR were 41.7% (26.1-75.9) and 16.6% (3.2-34.4). Conclusions: The kidney protective effect of dapagliflozin in patients with CKD is associated with its effects on albuminuria and hematocrit. Funding: Commercial Support - AstraZeneca