TY - JOUR
T1 - Glomerular and tubular effects of dapagliflozin, eplerenone and their combination in patients with chronic kidney disease
T2 - A post-hoc analysis of the ROTATE-3 study
AU - Lieverse, Tom T G F
AU - Puchades, Maria J
AU - Mulder, Udo D J
AU - Provenzano, Michele
AU - Krenning, Guido
AU - Jongs, Niels
AU - Wink, Simon E
AU - Slart, Riemer H J A
AU - Andreucci, Michele
AU - D'Marco, Luis
AU - De Nicola, Luca
AU - Gorriz, Jose L
AU - Heerspink, Hiddo J L
N1 - © 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
PY - 2024/2
Y1 - 2024/2
N2 - AIM: Sodium-glucose co-transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function.METHODS: This post-hoc analysis utilized data of the ROTATE-3 study, a randomized cross-over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro-hormonal markers and tubular sodium handling were assessed with mixed repeated measures models.RESULTS: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin-eplerenone was -34.8% (95% CI -52.2, -10.9), -5.9% (95% CI -32.5, 31.3) and -28.1% (95% CI -48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin-eplerenone [32.2% (95% CI -1.5, 77.4)], compared with dapagliflozin [-12.5% (95% CI -35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin-eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI -10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI -879.2, -32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI -926.1, -120.0). Dapagliflozin-eplerenone decreased proximal absolute sodium reabsorption [-971.0 mmol/min (95% CI -1411.0, -531.0)], but did not affect distal absolute sodium reabsorption [-9.2 mmol/min (95% CI -402.0, 383.6)].CONCLUSIONS: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects.
AB - AIM: Sodium-glucose co-transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function.METHODS: This post-hoc analysis utilized data of the ROTATE-3 study, a randomized cross-over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro-hormonal markers and tubular sodium handling were assessed with mixed repeated measures models.RESULTS: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin-eplerenone was -34.8% (95% CI -52.2, -10.9), -5.9% (95% CI -32.5, 31.3) and -28.1% (95% CI -48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin-eplerenone [32.2% (95% CI -1.5, 77.4)], compared with dapagliflozin [-12.5% (95% CI -35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin-eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI -10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI -879.2, -32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI -926.1, -120.0). Dapagliflozin-eplerenone decreased proximal absolute sodium reabsorption [-971.0 mmol/min (95% CI -1411.0, -531.0)], but did not affect distal absolute sodium reabsorption [-9.2 mmol/min (95% CI -402.0, 383.6)].CONCLUSIONS: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects.
KW - Adult
KW - Humans
KW - Eplerenone/therapeutic use
KW - Renal Insufficiency, Chronic/complications
KW - Benzhydryl Compounds/pharmacology
KW - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
KW - Sodium
KW - Heparitin Sulfate/pharmacology
KW - Glomerular Filtration Rate
KW - Diabetes Mellitus, Type 2/metabolism
U2 - 10.1111/dom.15346
DO - 10.1111/dom.15346
M3 - Article
C2 - 37926904
SN - 1462-8902
VL - 26
SP - 576
EP - 582
JO - Diabetes obesity & metabolism
JF - Diabetes obesity & metabolism
IS - 2
ER -