Tue. Oct 12th, 2021

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Background

Reductions in albuminuria are associated with a subsequent lower risk of kidney failure
in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly
reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney
function. Whether this effect persists in patients with chronic kidney disease with
and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on
albuminuria in patients with chronic kidney disease with and without type 2 diabetes
in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease
(DAPA-CKD) trial.

Methods

DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done
at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic
kidney disease, defined as an estimated glomerular filtration rate (eGFR) between
25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6
to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca;
Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered,
fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio.
Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression
in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria
or normoalbuminuria (ClinicalTrials.gov, NCT03036150.

Findings

Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly
assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949
mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric
mean UACR by 29·3% (95% CI –33·1 to –25·2; p<0·0001); relative to placebo, treatment
with dapagliflozin resulted in a geometric mean percentage change of −35·1% (95% CI
−39·4 to −30·6; p<0·0001) in patients with type 2 diabetes and −14·8% (−22·9 to −5·9;
p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin
increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60
to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin
decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions
in UACR at day 14 during dapagliflozin treatment were significantly associated with
attenuated eGFR decline during subsequent follow-up (β per log unit UACR change –3·06,
95% CI –5·20 to –0·90; p=0·0056).

Interpretation

In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin
significantly reduced albuminuria, with a larger relative reduction in patients with
type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients
with or without type 2 diabetes, but different effects on UACR, suggest that part
of the protective effect of dapagliflozin in patients with chronic kidney disease
might be mediated through pathways unrelated to reduction in albuminuria.

Funding

AstraZeneca.

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