Effects of dapagliflozin on volume status and systemic haemodynamics in patients with chronic kidney disease without diabetes: Results from DAPASALT and DIAMOND

Taha Sen, Rosalie Scholtes, Peter J. Greasley, David Z.I. Cherney, Claire C.J. Dekkers, Marc Vervloet, Alexander H.J. Danser, Sean J. Barbour, Cecilia Karlsson, Ann Hammarstedt, Qiang Li, Gozewijn D. Laverman, Petter Bjornstad, Daniel H. van Raalte, Hiddo J.L. Heerspink*

*Corresponding author for this work

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Abstract

Aims: To assess the effect of sodium-glucose cotransporter-2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes. Materials and methods: We performed a mechanistic open-label study (DAPASALT) to evaluate the effects of dapagliflozin on 24-hour sodium excretion, 24-hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo-controlled double-blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD. Results: In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m2, median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24-hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24-hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24-hour systolic BP decreased by −9.3 (95% confidence interval [CI] −19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash-out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m2, median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI −5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L). Conclusions: During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24-hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra-renal compensatory mechanisms to prevent excessive water loss.

Original languageEnglish
Pages (from-to)1578-1587
Number of pages10
JournalDiabetes, Obesity and Metabolism
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

ACKNOWLEDGMENTS:
T.S. is supported by the BEAt‐DKD project. The BEAt‐DKD project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no 115974. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations. D.Z.I.C. is supported by the Canadian Institutes of Health Research (CIHR) Kidney Foundation of Canada Team Grant Program, a Department of Medicine, University of Toronto Merit Award and also receives support from the Heart and Stroke Richard Lewar Centre of Excellence, the Heart and Stroke Foundation and the Kidney Foundation of Canada, and received trainee support from the Department of Medicine Eliot Phillipson Clinician Scientist Training Program, the Banting and Best Diabetes Centre at the University of Toronto, and the CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Research Award Program. P.B. receives salary and research support from National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Disease (R01 DK129211, R21 DK129720, K23 DK116720, UC DK114886 and P30 DK116073), JDRF (2‐SRA‐2019‐845‐S‐B, 3‐SRA‐2017‐424‐M‐B, 3‐SRA‐2022‐1097‐M‐B), Boettcher Foundation, American Heart Association (20IPA35260142), Center for Women's Health Research at University of Colorado, the Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine. H.J.L.H. is supported by a VIDI (917.15.306) grant from the Netherlands Organization for Scientific Research.

Publisher Copyright: © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

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