Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial

Abstract

Aims/hypothesis: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories.

Methods: DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25-75 ml min^-1 [1.73 m]^-2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200-5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories.

Results: Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories.

Conclusion/interpretations: The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity.

Trial registration: ClinicalTrials.gov NCT03036150.

Funding: The study was funded by AstraZeneca.

Keywords: Albuminuria; Dapagliflozin; KDIGO risk categories; Kidney outcome; SGLT2 inhibitor; eGFR.

Fig. 1

Number of patients by modified KDIGO risk categories. The KDIGO risk categories refer to a modified categorisation that includes an additional category of moderately high risk

Fig. 2

Relative effect and absolute risk reduction for dapagliflozin on the primary and secondary outcomes across different subgroups of KDIGO risk categories. The primary composite outcome is a composite of an eGFR decline of ≥50%, ESKD or death from kidney or cardiovascular causes. The kidney composite outcome is a composite of an eGFR decline of ≥50%, ESKD or death from kidney causes

Fig. 3

Effects of dapagliflozin on the primary composite outcomes across KDIGO risk categories and subgroups of UACR and eGFR in patients with diabetes (a) and without diabetes (b). The primary composite outcome is a composite of an eGFR decline of ≥50%, ESKD or death from kidney or cardiovascular causes

Fig. 4

Effect of dapagliflozin on eGFR slope across KDIGO risk categories. LS, least squares. Data reported with 95% CI

Fig. 5

Effect of dapagliflozin on the primary composite outcome across baseline UACR levels in patients with diabetes (a) and without diabetes (b). The solid line indicates the HR for the primary outcome across baseline UACR, on the left y-axis plotted on a natural log scale; the shaded area indicates the 95% CI. The histogram shows the distribution of UACR at baseline, by number of participants on the right y-axis