TY - JOUR
T1 - Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and their Combination in Patients with Chronic Kidney Disease
T2 - A Randomized Cross-Over Clinical Trial
AU - ROTATE-3 study group
AU - Provenzano, Michele
AU - Puchades, Maria Jesús
AU - Garofalo, Carlo
AU - Jongs, Niels
AU - D'Marco, Luis
AU - Andreucci, Michele
AU - De Nicola, Luca
AU - Gorriz, Jose Luis
AU - Heerspink, Hiddo J L
N1 - Copyright © 2022 by the American Society of Nephrology.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - BACKGROUND: SGLT2 inhibitors and MRAs reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with chronic kidney disease (CKD). We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and mineralocorticoid receptor antagonists (MRA) eplerenone alone and in combination in patients with CKD.METHODS: We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hours, eGFR 30-90 ml/min per 1.73 m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline.RESULTS: Of 57 patients screened, 46 were randomly assigned (mean eGFR 58.1 ml/min per 1.73 m2, median UACR 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% CI, -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; P<0.001 versus dapagliflozin; P=0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (r=-0.13; P=0.47; r=-0.08; P=0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (n=8; 17.4%) compared with dapagliflozin (n=0; 0%) or dapagliflozin-eplerenone (n=2; 4.3%; P between-groups=0.003).CONCLUSIONS: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: European Union Clinical Trials Register, EU 2017-004641-25.
AB - BACKGROUND: SGLT2 inhibitors and MRAs reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with chronic kidney disease (CKD). We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and mineralocorticoid receptor antagonists (MRA) eplerenone alone and in combination in patients with CKD.METHODS: We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hours, eGFR 30-90 ml/min per 1.73 m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline.RESULTS: Of 57 patients screened, 46 were randomly assigned (mean eGFR 58.1 ml/min per 1.73 m2, median UACR 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% CI, -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; P<0.001 versus dapagliflozin; P=0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (r=-0.13; P=0.47; r=-0.08; P=0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (n=8; 17.4%) compared with dapagliflozin (n=0; 0%) or dapagliflozin-eplerenone (n=2; 4.3%; P between-groups=0.003).CONCLUSIONS: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: European Union Clinical Trials Register, EU 2017-004641-25.
U2 - 10.1681/ASN.2022020207
DO - 10.1681/ASN.2022020207
M3 - Article
C2 - 35440501
SN - 1046-6673
VL - 33
SP - 1
EP - 12
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 6
ER -