A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function

Hiddo J.l Heerspink ,Peter Rossing ,Dapa-Ckd Trial Committees ,David Z.i Cherney ,Glenn M Chertow ,David C Wheeler ,Robert D Toto ,Mikhail Kosiborod ,Bergur V Stefánsson ,Jamie P Dwyer ,Anna Maria Langkilde ,John J.v Mcmurray ,Ricardo Correa–Rotter ,Douwe Postmus ,C David Sjöström ,Tom Greene ,Investigators

doi:10.1016/j.kint.2021.09.005

Abstract

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function.

Highlights

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria
Given that there were fewer doubling of serum creatinine events in the dapagliflozin group compared to the placebo group, and that these events were associated with end-stage kidney disease (ESKD) and mortality, we explored whether the beneficial effect of dapagliflozin on ESKD and mortality could be explained by its reduction in risk of abrupt declines in kidney function
Prior to the availability of data from cardiovascular safety trials, there was concern among some clinicians that the abrupt rise in creatinine might be a signal of harm related to Acute kidney injury (AKI) that had a deleterious effect on survival—an effect amplified in the presence of CKD and increased albuminuria.[4,5]

Summary

Introduction

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. During the early stages of development of SGLT2 inhibitors, concerns were raised that these agents could increase the risk of AKI resulting from hypovolemia, treatment-induced acute reduction in glomerular filtration rate (GFR), and the potential to trigger kidney medullary hypoxic injury These concerns were supported by early case reports suggesting that risk of AKI is higher among patients with type 2 diabetes mellitus and preserved kidney function who initiated SGLT2 inhibitors.[6] large cardiovascular and kidney outcome trials demonstrated that SGLT2 inhibitors could reduce the risk of AKI. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial demonstrated that the SGLT2 inhibitor dapagliflozin reduced the risk of kidney failure and heart failure hospitalization, and prolonged survival in patients with CKD with and without type 2 diabetes.[9] In this analysis, we report the effect of dapagliflozin on abrupt declines in kidney function These events were captured in the DAPACKD trial as a pre-specified exploratory outcome, defined as the doubling of serum creatinine between 2 subsequent visits. We compare the frequency of serious AKI adverse events (as reported by investigators) in patients randomized to receive either dapagliflozin or placebo

Methods

Results

Conclusion