without diabetes mellitus (DM).

Study Design

Eligible patients were randomized in a 1:1 fashion to either dapagliflozin 10 mg

daily (n = 2,152) or placebo (n = 2,152). 
Total number of enrollees: 4,304
Duration of follow-up: 2.4 years
Mean patient age: 61.8 years
Percentage female: 33.1%
Dapagliflozin And Prevention of Adverse Inclusion criteria:
outcomes in Chronic Kidney Disease - DAPA- ≥18 years of age
Urinary albumin:creatinine ratio ≥200 mg/g
CKD Estimated glomerular filtration rate (eGFR) between 25 and 75 ml/min/1.73 m2
Stable and, for the patient, maximum tolerated labelled dose of angiotensin-
Feb 06, 2023
converting enzyme inhibitors or angiotensin-receptor blockers for ≥4 weeks,
unless contraindicated
Author/Summarized by Dharam J. Kumbhani, MD, SM, FACC
Author: Exclusion criteria:

Summary Reviewer: Deepak L. Bhatt, MD, MPH, FACC Type 1 DM

Trial Sponsor:
Date Presented:
Date Published:
Date Updated:
Original Posted Date:
References
Contribution To Literature:
Autosomal dominant or autosomal recessive polycystic kidney disease, lupus
AstraZeneca nephritis, or ANCA-associated vasculitis
Receiving cytotoxic therapy, immunosuppressive therapy, or other
08/23/2021
immunotherapy for primary or secondary renal disease within 6 months prior
12/06/2022 to enrollment
New York Heart Association class IV congestive heart failure (HF)
02/06/2023 Myocardial infarction, unstable angina, stroke, or transient ischemic attack
08/30/2020 within 8 weeks prior to enrollment
Coronary revascularization (percutaneous coronary intervention or coronary
artery bypass grafting) or valvular repair/replacement within 8 weeks prior to
enrollment

Highlighted text has been updated as of December 20, 2022. Other salient features/characteristics:

The DAPA-CKD trial showed that dapagliflozin results in salutary effects on renal Mean blood pressure: 138/78 mm Hg
function and mortality among patients with CKD, irrespective of DM status. Mean eGFR: 43 ml/min/1.73 m2; eGFR <30: 14%, 30-<45: 44%, 45-<60: 31%
Urinary albumin-to-creatinine ratio >1000: 48%
Description:
Principal Findings:
The goal of the trial was to assess the safety and efficacy of dapagliflozin in
reducing renal events among patients with chronic kidney disease (CKD) with or
The trial stopped early due to benefit. The primary endpoint, decline in eGFR
≥50%, end-stage kidney disease, death from renal causes, or cardiovascular (CV)
death for dapagliflozin vs. placebo, was 9.2% vs. 14.5% (hazard ratio [HR] 0.61,
95% confidence interval [CI] 0.51-0.72; p = 0.000000028). The benefit of
dapagliflozin on the primary endpoint was consistent in patients with and without
type 2 DM.
Decline in eGFR ≥50%: 5.2% vs. 9.3%
End-stage kidney disease: 5.1% vs. 7.5%
CV death: 3.0% vs. 3.7% (p > 0.05)
Secondary outcomes for dapagliflozin vs. placebo:
CV death/HF hospitalization: 4.6% vs. 6.4% (p = 0.0009)
All-cause mortality: 4.7% vs. 6.8% (p = 0.003)
Amputation: 1.6% vs. 1.8% (p = 0.73)
Major hypoglycemia: 0.7% vs. 1.3% (p = 0.04)
Presence of CV disease: Results for primary endpoint, CV disease/HF, all-cause
mortality and other CV outcomes for dapagliflozin vs. placebo were maintained
among patients with and without known CV disease at baseline (p for interaction >
0.05 for all); event rates were higher among patients with known CV disease.
Cause-specific mortality: 36.8% due to CV causes, 41.3% due to non-CV causes,
remainder undetermined. For dapagliflozin vs. placebo, CV death: 1.9% vs. 2.3% (p
= 0.34); non-CV death: 1.7% vs. 3.1% (p = 0.003).
Serious infections: 9.0% vs. 9.6% (p = 0.49); mortality in this subgroup for
dapagliflozin vs. placebo: 7.8% vs. 15.0% (p < 0.05)
Malignancy: 2.7% vs. 3.3% (p = 0.29); mortality in this subgroup: 15.3% vs.
23.9% (p > 0.05)
Presence of heart failure (HF) (n = 468): Dapagliflozin reduced the risk of the
primary endpoint equally in patients with HF (HR 0.58, 95% CI 0.37-0.91) and
without HF (HR 0.62, 95% CI 0.51-0.75) (p for interaction = 0.59). Similar results
were noted for HF/CV hospitalization, all-cause mortality, and HF hospitalization (p
for interaction > 0.05). Event rates were higher among patients with HF.
Effect on hospitalizations: First hospitalization for any cause for dapagliflozin vs.
placebo: HR 0.84, 95% CI 0.75-0.94; first hospitalization or death: HR 0.83, 95% CI
0.75-0.93; all hospitalizations or death: rate ratio 0.79, 95% CI 0.70-0.89. There was
no interaction by diabetes status.
Interpretation:
The results of this trial indicate that dapagliflozin results in salutary effects on
renal function among patients with CKD, with or without DM, who are already on
maximal tolerated doses of angiotensin-converting enzyme inhibitor/angiotensin-
receptor blocker. There were also beneficial effects noted on non-CV and all-cause
mortality and all-cause hospitalizations. Results were sustained among patients
with or without known CV disease or HF at baseline.
Even though the sodium–glucose co-transporter 2 (SGLT2) inhibitors were
introduced as type 2 DM management drugs, results of DAPA-CKD and similar
studies indicated a clear benefit in CKD management. This trial enrolled a
dedicated CKD population, and conclusively shows a benefit in this patient
population, irrespective of DM status. These drugs will likely change practice and
have a prominent role in future CKD management guidelines. The CREDENCE trial
showed a similar benefit in CKD patients with type 2 DM; this trial extends the
benefit to patients without DM and with lower GFR. Similar results have been
reported for heart failure reduction among patients with heart failure and
reduced ejection fraction with these drugs, independent of DM status.
References:
Schechter M, Jongs N, Chertow GM, et al. Effects of Dapagliflozin on
Hospitalizations in Patients With Chronic Kidney Disease: A Post Hoc Analysis of
DAPA-CKD. Ann Intern Med 2023;176:59-66.
McMurray JJ, Wheeler DC, Stefánsson BV, et al., on behalf of the DAPA-CKD Trial
Committees and Investigators. Effects of Dapagliflozin in Patients With Kidney
Disease, With and Without Heart Failure. JACC Heart Fail 2021;9:807-20.
Poster presented by Dr. John J.V. McMurray at the European Society of Cardiology
Virtual Congress, August 23, 2021.
Heerspink HJ, Sjöström CD, Jongs N, et al. Effects of Dapagliflozin on Mortality in
Patients With Chronic Kidney Disease: A Pre-specified Analysis From the DAPA-CKD
Randomized Controlled Trial. Eur Heart J 2021;42:1216-27.
Editorial Comment: Marx N, Floege J. Dapagliflozin, Advanced Chronic Kidney
Disease, and Mortality: New Insights From the DAPA-CKD Trial. Eur Heart J
2021;42:1228-30.
McMurray JJ, Wheeler DC, Stefánsson BV, et al., on behalf of the DAPA-CKD Trial
Committees and Investigators. Effect of Dapagliflozin on Clinical Outcomes in
Patients With Chronic Kidney Disease, With and Without Cardiovascular Disease.
Circulation 2021;143:438-48.