Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease - DAPA-CKD

Contribution To Literature:

Highlighted text has been updated as of August 23, 2021.

The DAPA-CKD trial showed that dapagliflozin results in salutary effects on renal function and mortality among patients with CKD, irrespective of DM status.

Description:

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 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%

Inclusion criteria:

  • ≥18 years of age
  • Urinary albumin:creatinine ratio ≥200 mg/g
  • 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-converting enzyme inhibitors or angiotensin-receptor blockers for ≥4 weeks, unless contraindicated

Exclusion criteria:

  • Type 1 DM
  • Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis
  • Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrollment
  • New York Heart Association class IV congestive heart failure (HF)
  • Myocardial infarction, unstable angina, stroke, or transient ischemic attack 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

Other salient features/characteristics:

  • Mean blood pressure: 138/78 mm Hg
  • Mean eGFR: 43 ml/min/1.73 m2; eGFR <30: 14%, 30-<45: 44%, 45-<60: 31%
  • Urinary albumin-to-creatinine ratio >1000: 48%

Principal Findings:

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.

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. 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:

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;Aug 23:[Epub ahead of print].

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.

Presented by Dr. John J. V. McMurray at the American Heart Association Virtual Scientific Sessions, November 13, 2020.

Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al., on behalf of the DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients With Chronic Kidney Disease. N Engl J Med 2020;383:1436-46.

Presented by Dr. Hiddo J.L. Heerspink at the European Society of Cardiology Virtual Congress, August 30, 2020.

Rationale and protocol: Heerspink HJ, Stefansson BV, Chertow GM, et al., on behalf of the DAPA-CKD Investigators. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant 2020;35:274-82.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure

Keywords: ESC21, ESC Congress, AHA20, AHA Annual Scientific Sessions, ESC20, Diabetes Mellitus, Glomerular Filtration Rate, Heart Failure, Kidney Diseases, Metabolic Syndrome, Primary Prevention, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2


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