CONFERENCE UPDATE: ASN 2023

Identifying the mediators of dapagliflozin-induced renal benefits in patients with CKD with or without T2DM: Post-hoc analysis of the DAPD-CKD trial

NEPHROLOGY
19 Feb 2024

Study Design

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), has been shown to induce renal, cardiovascular (CV), and survival benefits in patients with chronic kidney disease (CKD), regardless of the presence of type 2 diabetes mellitus (T2DM) in the DAPA-CKD trial.1 Separate mediation analyses performed using clinical data from patients with T2DM revealed that the renal benefits of SGLT2is can be attributed to several key mediators such as hemoglobin, urinary albumin-to-creatinine ratio (UACR), and serum urate.1 Nonetheless, whether these mediators are involved in facilitating the observed kidney-protective benefits of dapagliflozin in patients with CKD with or without T2DM remained unclear.1

A post-hoc analysis of the DAPA-CKD trial was conducted to examine the potential mediators of the observed kidney-protective effects of dapagliflozin in patients with CKD, with or without T2DM.1 A total of 4,304 adult participants with CKD, with or without T2DM, with an estimated glomerular filtration rate (eGFR) of 25mL/min/1.73m2-75mL/min/1.73m2 and UACR of 200mg/g-5000mg/g were randomized to receive dapagliflozin 10mg daily (n=2,152) or placebo (n=2,152) with a median follow-up of 2.4 years.1 Biomarkers including UACR, hematocrit, blood pressure (BP), body weight, heart rate, HbA1c, serum potassium, and serum sodium levels were examined throughout the study.1

The primary endpoint was a composite of ≥50% sustained eGFR decline, end-stage kidney disease (ESKD), or CV- or renal-related deaths.1 The prespecified kidney outcome encompassed outcomes of the primary endpoint, excluding CV death.1

Primary outcome: 

  • The primary outcome was a composite of ≥50% sustained eGFR decline, ESKD, or death from a kidney or CV cause1
  • Fewer patients in the dapagliflozin arm experienced the primary outcome compared to those who received placebo (9.2% vs. 14.4%)1
  • UACR, hematocrit, and systolic blood pressure (SBP) were found to be the key mediators of dapagliflozin’s effect on the primary outcome, which explained up to 35.4%, 35.5% and 1.7% of the effect, respectively1
  • Among patients with T2DM, UCAR (41.7%) and hematocrit (31.2%) remained the dominant key mediators of dapagliflozin’s effect on the primary outcomes1
  • Dapagliflozin’s effect on the primary outcome facilitated by changes in UACR and SBP were evident 2 weeks after treatment initiation and were sustained at 4 months1
  • Dapagliflozin’s effect on the primary outcome facilitated by changes in hematocrit were evident 2 months after treatment initiation and were sustained at 4 months1

Kidney outcome:

  • Kidney outcome included all components of the composite primary outcome, excluding CV death, i.e. a composite of ≥50% sustained eGFR decline, ESKD, or kidney-related death1
  • Fewer patients in the dapagliflozin arm experienced kidney outcomes was lower in the dapagliflozin arm compared to the placebo arm (6.6% vs. 11.3%)1
  • UACR, hematocrit and SBP were identified as the key mediators of dapagliflozin’s effect on kidney outcomes, contributing up to 39.6%, 33.5% and 4.6% of the effect, respectively1
  • Among patients with T2DM, UCAR (43.8%) and hematocrit (25.2%) remained the dominant key mediators of dapagliflozin’s effect on kidney outcomes1
  • Dapagliflozin’s effect on the kidney outcome facilitated by changes in UACR and SBP were evident 2 weeks after treatment initiation and were sustained at 4 months1
  • Dapagliflozin’s effect on the kidney outcome facilitated by changes in hematocrit were evident 2 months after treatment initiation and were sustained at 4 months1
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