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):1436-1446.
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Clinical Question

In patients with or without type 2 diabetes and chronic kidney disease characterized by eGFR reduction and microalbuminuria, does dapagliflozin affect the progression of chronic kidney disease and cardiovascular death?

Bottom Line

In patients with chronic kidney disease characterized by at eGFR reduction and microalbuminuria with and without type 2 diabetes, treatment with dapagliflozin was associated with less progression of CKD, renal mortality, or CVD mortality, when compared to placebo. Of note, there was also a reduction in all-cause mortality with dapagliflozin, but it wasn't a primary endpoint.

Major Points

CKD is a risk factor for death among adults, regardless of diabetes status.[1] Few options exist to prevent progression of CKD and reduce the risk of CKD-associated death. For example, ACE-inhibitors and ARBs may prevent progression of progression to albuminuria but do not clearly alter changes in serum creatinine.[2] There is an urgent need to identify potential mechanisms to prevent progression of CKD.

SGLT2 inhibitors promote glucosuria and were brought to market as oral diabetes medications. The benefit of these agents extended beyond changes in Hgb A1c, as empagliflozin lowered CVD events in the 2015 EMPA-REG OUTCOME study. This study also assessed CKD events in secondary outcomes and found the medication to lower risk of CKD events. For example, empagliflozin incident or worsening nephropathy (HR 0.61; 95% CI 0.53-0.70), progression to macroalbuminuria (0.62; 0.54-0.72), doubling of serum creatinine (0.56; 0.39-0.79). EMPA-REG OUTCOME included only diabetes, and whether this benefit also existed for adults without T2DM was unclear.

Published in 2020, the Dapagliflozin in Chronic Kidney Disease (DAPA-CKD) randomized 4,304 patients with CKD (defined by eGFR of 25 to 75 and albuminuria with ACR of 200 to 5000 mg/g) with and without T2DM to dapagliflozin or placebo. The study was halted early after an interim safety analysis found evidence of benefit as dapagliflozin was found to reduce the composite endpoint of decline of ≥50% in eGFR, new ESRD, renal mortality, or CVD mortality (9.2% vs. 14.5%; HR 0.61; 95% CI 0.51-0.72; NNT=19). Importantly, this benefit was similar regardless of T2DM status. The medication was also associated with reduction in other endpoints, including all-cause mortality (4.7% vs. 6.8%; 0.69; 0.53-0.88; NNT=48). There was a slightly higher risk of major hypoglycemia (0.7% vs. 1.3%; P=0.04; NNH=166) with dapagliflozin use.

Together, DAPA-CKD provides a new potential intervention for prevention of CKD progression among adults with CKD and at least some microalbuminuria (at least KDIGO CKD stage G2A2 severity). It might also reduce mortality in this population.

Guidelines

As of October 2020, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, randomized, placebo controlled trial
  • N=4,304
    • Dapagliflozin (n=2,152)
    • Placebo (n=2,152)
  • Enrollment: 2017-2018
  • 450 study sites over 20 countries
  • Mean follow-up: 2.4 years (stopped early for benefit)
  • Analysis: Intention-to-treat
  • Primary outcome: Decline of ≥50% in eGFR, new ESRD, renal mortality, or CVD mortality

Population

Inclusion Criteria

  • Age ≥18 years old
  • eGFR ≥25 and ≤75 mL/min/1.73 m2
  • Urine ACR ≥200 and ≤5,000 mg/g at 1st visit
  • On maximum daily dose with ACE inhibitor or ARB for at least 4 weeks before visit 1
  • With or without type 2 diabetes

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 symptoms
  • MI, Unstable angina, stroke or TIA within 12 weeks
  • Coronary revascularization (PCI, CABG) or 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

From the dapagliflozin group

  • Mean age: 62 years old
  • Female: 33%
  • Mean BMI: 29.5 kg/m2
  • Blood pressure 137/77 mm Hg
  • eGFR: mean 43 mL/min/1.73 m2
    • eGFR ≥60 11%
    • eGFR 45-60 30%
    • eGFR 30-45 46%
    • eGFR <30 14%
  • Urine Albumin-to-creatinine ratio: 965 mg/g
    • ACR >1000 mg/g: 48%
  • Type 2 diabetes: 68%
  • Cardiovascular disease 38%
  • Heart Failure: 11%
  • Previous Medications
    • ACE Inhibitor: 31%
    • ARB: 67%
    • Diuretic: 43%
    • Statin: 65%

Interventions

  • Randomized to a group
    • Dapagliflozin at 10 mg once daily
    • Placebo
  • Follow-up at 2 weeks and months 2, 4, and 8 then at 4 month intervals.

Outcomes

Dapagliflozin 10 mg once daily vs. placebo therapy.

Primary Outcomes

Decline of ≥50% in eGFR, new ESRD, renal mortality, or CVD mortality
9.2% vs. 14.5% (HR 0.61; 95% CI 0.51-0.72; P<0.001; NNT=19)
Subcomponents of above were not considered as primary outcomes but are presented here for clarity.
Decline of ≥50% in eGFR: 5.2% vs. 9.3% (HR 0.53; 95% CI 0.42–0.67)
New ESRD: 5.1% vs. 7.5% (HR 0.64; 95% CI 0.50–0.82)
eGFR of <15 ml/min/1.73 m2: 3.9% vs. 5.6% (HR 0.67; 95% CI 0.51–0.88)
Long-term dialysis: 3.2% vs. 4.6% (HR 0.66; 95% CI 0.48–0.90)
Kidney transplantation: 0.1% vs. 0.4%
Renal mortality: <0.1% vs. 0.3%
CVD mortality: 3.0% vs. 3.7% (HR 0.81; 95% 0.58–1.12)

Secondary Outcomes

Decline of ≥50% in eGFR, new ESRD, renal mortality
6.6% vs. 11.3% (HR 0.56; 95% CI 0.45-0.68; P<0.001)
CVD mortality or HR hospitalization
4.6% vs. 6.4% (HR 0.71; 95% CI 0.55-0.92; P=0.009)
All-cause mortality
4.7% vs. 6.8% (HR 0.69; 95% CI 0.53-0.88; P=0.004; NNT=48)

Subgroup Analysis

The primary outcome was similar by age strata, sex, race, geographic region, type 2 diabetes status, eGFR strata, and SBP strata.

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; NNH=166)
Volume depletion
5.9% vs. 4.2% (P=0.01)

Criticisms

  • The trial was stopped early due to data showing benefits, so it may have led to underpowering of less common endpoints.
  • 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.
  • Patients needed at least some microalbuminuria, so unclear efficacy of this medication among those with CKD with only eGFR reduction and no microalbuminuria.

Funding

AstraZeneca (manufacturers of Farxiga, the brand name for dapagliflozin)

Further Reading

  1. Tonelli M et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 2006. 17:2034-47.
  2. Trietley GS et al. Clinical Inquiry: Do ACE inhibitors or ARBs help prevent kidney disease in patients with diabetes and normal BP?. J Fam Pract 2017. 66:257-263.