DAPA-CKD

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Heerspink, et al. "Dapagliflozin in Patients with Chronic Kidney Disease". The New England Journal of Medicine. 2020. 383(13):***.
PubMedFull textPDFClinicalTrials.gov

Clinical Question

In patients with or without type 2 diabetes, does dapagliflozin affect the progression of chronic kidney disease?

Bottom Line

In patients treated with dapagliflozin, there was a decrease in the the decline of estimated GFR, progression of end-stage kidney disease and decreased death from renal or cardiovascular causes when compared to placebo, regardless of the status of diabetes.

Major Points

DAPA-CKD is the first study showing the renal protective effects of SGLT2 inhibitors in patients with CKD without type 2 diabetes. This builds on previous trials such as DAPA-HF and CREDENCE that show the cardiorenal benefits of this class of medications. This is a paradigm shift in thinking of these as diabetes medications and more as cardiorenal medications that also happens to be used in diabetes. DAPA-CKD demonstrates a significant effect seen early on with the initiation of these medications on clinically relevant outcomes (almost 40% reduction in CKD progression). This study will change how we view SGLT2 inhibitors as a cornerstone therapy for multiple disciplines (cardiology, endocrinology, nephrology) in managing these conditions.

Guidelines

Design

  • Multicenter, double-blind, randomized, placebo controlled trial
  • N=4304
    • Dapagliflozin (n=2,152)
    • Placebo (n=2,152)
  • Enrollment: 7517 participants
  • 450 study sites over 20 countries
  • Mean follow-up: 2.4 years - stopped early due to benefit
  • Analysis: Intention-to-treat
  • Primary outcome: Composite outcome of first occurrence of the following (time-to-event analysis)
    • Decline of >50% in estimated GFR
    • Onset of end-stage kidney disease (dialysis > 28 days, kidney transplantation or estimated GFR <15ml/min
    • death from renal or cardiovascular causes
  • Secondary outcome: Time to first occurence
    • Sustained decline in estimated GFR or at least 50%, end-stage kidney disease, renal death
    • composite cardiovascular outcomes (hospitalization for heart failure, death from cardiovascular cause)
    • death from any cause

Population

Inclusion Criteria

  • Age > 18 years old
  • eGFR > 25 and 75 ml/min
  • Urine ACR >200 and <5000 mg/g at 1st visit
  • Stable for maximum daily dose with ACE inhibitor or ARB for at least 4 weeks before visit 1
  • Type 2 diabetes mellitus

Exclusion Criteria

  • Type 1 Diabetes
  • Specific Kidney Conditions (Polycystic kidney disease, Lupus Nephritis, ANCA vasculitis)
  • History of organ transplantation
  • Received immunotherapy for primary or secondary kidney disease within 6 months
  • NYHA Class IV Congestive Heart Failure
  • MI, Unstable angina, stroke or TIA within 12 weeks'
  • Coronary revascularization of bypass / valvular repair within 12 weeks
  • Any medical condition (eg. malignancy) such that life expectancy is less than 2 years
  • Active malignancy requiring treatment
  • Hepatic impairment

Baseline Characteristics

  • Mean age: 62 years old
  • Female: 32%
  • Mean BMI: 29.5
  • Blood pressure 137/77
  • Estimated GFR: mean 43
  • Urine Albumin-to-creatinine ratio - 965, with 48% >1000
  • Type 2 Diabetes: 67%
  • Cardiovascular disease 37%
  • Heart Failure: 11%
  • Previous Medications
    • ACE Inhibitor: 31%
    • ARB: 67%
    • Diuretic: 43%
    • Statin: 65%

Interventions

  • Randomized to dapagliflozin 10 mg once daily or placebo

Outcomes

Dapagliflozin 10 mg once daily vs. placebo therapy.

Primary Outcomes

Composite sustained decline in estimated GFR, end-stage kidney disease, death from renal causes
9.2% % vs. 14.5 % (HR 0.61; 95% CI 0.51-0.72; P<0.001)

Secondary Outcomes

Composite of decline in estimated GFR, end-stage kidney disease, death from renal cause
6.6% vs. 11.3% (HR 0.56; 95% CI 0.45-0.68; P=<0.001)
Composite of death from cardiovascular cause or hospitalization for heart failure
4.6% vs. 6.4% (HR 0.71; 95% CI 0.55-0.92; P=0.009)
Death from any Cause
4.7% vs. 6.8% (HR 0.69; 95% CI 0.53-0.88; P=0.004)

Subgroup Analysis

Patients with diabetes
11.9% vs. 15.7% (HR 0.64; 95% CI 0.52-0.79)
Patients without diabetes
6.45% vs. 10.5% (HR 0.50; 95% CI 0.35-0.72)
Estimated GFR < 45ml/min
11.9% vs. 17.36% (HR 0.63; 95% CI 0.51-0.78)
Estimated GFR > 45ml/min
5.11% vs. 10.5% (HR 0.49; 95% CI 0.34-0.69)
Urinary albumin-to-creatinine ratio <1000
3.98% vs. 7.49% (HR 0.54; 95% CI 0.37-0.77)
Urinary albumin-to-creatinine ratio >1000
14.59% vs. 15.39% (HR 0.62; 95% CI 0.50-0.76)

Adverse Events

Discontinuation of regimen due to adverse event
5.5% vs. 5.7% (P=0.79)
Any serious adverse event
29.5% vs. 33.9% (P=0.002)
Amputation
1.6% vs. 1.8% (P=0.73)
Definite or probably diabetic ketoacidosis
0% vs. <0.1% (P=0.50)
Fracture
4.0% vs. <3.2% (P=0.22)
Renal-related adverse event
7.2% vs. <8.7% (P=0.07)
Major hypoglycemia
0.7% vs. <1.3% (P=0.04)
Volume depletion
5.9% vs. <4.2% (P=0.01)

Criticisms

  • The trial was stopped early due to data showing benefits. This may have reduced the power of the study.
  • Similar to CREDENCE, the initiation of an SGLT2 inhibitor was a initial dip in the estimated GFR.
  • Almost all patients were on an ACE inhibitor or ARB, so it's unclear if there is benefit to adding dapagliflozin for patients with CKD who are unable to take an ACE inhibitor or ARB.

Funding

AstraZeneca (producers of dapagliflozin)

Further Reading