학술논문
Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.
Document Type
Academic Journal
Author
Marton A; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore; Department of Internal Medicine 4-Nephrology and Hypertension, Paracelsus Private Medical School Nuremberg, Nuremberg, Germany. Electronic address: adriana.marton@duke-nus.edu.sg.; Saffari SE; Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore.; Rauh M; Research Laboratory, Division of Paediatrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.; Sun RN; Clinical Imaging Research Centre, Centre for Translational Medicine, Singapore.; Nagel AM; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany; German Cancer Research Center (DKFZ), Division of Medical Physics in Radiology, Heidelberg, Germany.; Linz P; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany.; Lim TT; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.; Takase-Minegishi K; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.; Pajarillaga A; Department of Laboratory Medicine, National University Hospital, Singapore.; Saw S; Department of Laboratory Medicine, National University Hospital, Singapore.; Morisawa N; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.; Yam WK; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.; Minegishi S; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.; Totman JJ; Clinical Imaging Research Centre, Centre for Translational Medicine, Singapore; Radiography and Medical Imaging Department, Fatima College of Health Sciences, Abu Dhabi, United Arab Emirates.; Teo S; Clinical Imaging Research Centre, Centre for Translational Medicine, Singapore.; Teo LLY; Department of Cardiology, National Heart Centre Singapore, Singapore.; Ng CT; Department of Cardiology, National Heart Centre Singapore, Singapore.; Kitada K; Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.; Wild J; Center for Cardiology, Cardiology I, Johannes Gutenberg-University, Mainz, Germany.; Kovalik JP; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.; Luft FC; Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Berlin, Germany.; Greasley PJ; Early Discovery and Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Chin CWL; Department of Cardiology, National Heart Centre Singapore, Singapore.; Sim DKL; Department of Cardiology, National Heart Centre Singapore, Singapore.; Titze J; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore; III. Department of Medicine and Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA. Electronic address: jens.titze@duke-nus.edu.sg.
Source
Publisher: Elsevier Biomedical Country of Publication: United States NLM ID: 8301365 Publication Model: Print Cited Medium: Internet ISSN: 1558-3597 (Electronic) Linking ISSN: 07351097 NLM ISO Abbreviation: J Am Coll Cardiol Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential.
Objectives: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment.
Methods: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance.
Results: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70).
Conclusions: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).
Competing Interests: Funding Support and Author Disclosures The DAPA-Shuttle1 study was an investigator-initiated trial funded by AstraZeneca via the externally sponsored scientific research program (ESR-18-13712; Principal Investigator: Dr Titze). The SSIS Project was realized with grant support from Duke-NUS Medical School (Duke-NUS-KBrFA/2019/0026) to Dr Titze. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr Titze has received one personal speaker fee from AstraZeneca in the past 4 years. Dr Greasley has been an employee of and shareholder in AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Objectives: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment.
Methods: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance.
Results: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70).
Conclusions: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).
Competing Interests: Funding Support and Author Disclosures The DAPA-Shuttle1 study was an investigator-initiated trial funded by AstraZeneca via the externally sponsored scientific research program (ESR-18-13712; Principal Investigator: Dr Titze). The SSIS Project was realized with grant support from Duke-NUS Medical School (Duke-NUS-KBrFA/2019/0026) to Dr Titze. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr Titze has received one personal speaker fee from AstraZeneca in the past 4 years. Dr Greasley has been an employee of and shareholder in AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)