Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial

Abstract

Background: Recent cardiovascular outcome trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes.

Methods: DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2-4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin-angiotensin system inhibitor at enrolment.

Results: After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05).

Conclusion: DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.

Keywords: chronic kidney disease; dapagliflozin; randomized controlled clinical trial; sodium–glucose co-transporter inhibitor.

Graphical Abstract

FIGURE 1

Countries participating in DAPA-CKD.

FIGURE 2

DAPA-CKD study diagram.

FIGURE 3

Proportion of patients with eGFR <60 mL/min/1.73 m² and UACR ≥300 mg/g in completed SGLT2 inhibitor trials compared with DAPA-CKD. Interim baseline data from DAPA-CKD (data cut September 2019) were used to create the figure.

FIGURE 4

National Kidney Foundation classification of chronic kidney disease. The UACR and eGFR range for enrolment in the CREDENCE (green), DAPA-CKD (blue) and EMPA-KIDNEY (purple) trials are shown. White-shaded area indicates the eGFR and UACR inclusion criteria in the DAPA-CKD trial. Cardiovascular outcome trials are indicated in the circles and positioned based on their mean eGFR and median UACR level.