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Water conservation overrides osmotic diuresis during SGLT2 inhibition in patients with heart failure

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Item Type:Article
Title:Water conservation overrides osmotic diuresis during SGLT2 inhibition in patients with heart failure
Creators Name:Marton, A. and Saffari, S.E. and Rauh, M. and Sun, R.N. and Nagel, A.M. and Linz, P. and Lim, T.T. and Takase-Minegishi, K. and Pajarillaga, A. and Saw, S. and Morisawa, N. and Yam, W.K. and Minegishi, S. and Totman, J.J. and Teo, S. and Teo, L.L.Y. and Ng, C.T. and Kitada, K. and Wild, J. and Kovalik, J.P. and Luft, F.C. and Greasley, P.J. and Chin, C.W.L. and Sim, D.K.L. and Titze, J.
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).
Keywords:Benzhydryl Compounds, Conservation of Water Resources, Diuresis, Glucose, Glucosides, Heart Failure, Left Ventricular Function, Osmotic Diuretics, Sodium, Sodium-Glucose Transporter 2, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume, Type 2 Diabetes Mellitus, Water
Source:Journal of the American College of Cardiology
Page Range:1386-1398
Date:16 April 2024
Official Publication:https://doi.org/10.1016/j.jacc.2024.02.020
PubMed:View item in PubMed

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