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Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure

Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, Lim TT, Takase-Minegishi K, Pajarillaga A, Saw S, Morisawa N, Yam WK, Minegishi S, Totman JJ, Teo S, Teo LL, Ng CT, Kitada K, Wild J, Kovalik JP, Luft FC, Greasley PJ, Chin CW, Sim DK, Titze J (2024)

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Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2024

Journal

Book Volume: 83

Pages Range: 1386-1398

Journal Issue: 15

DOI: 10.1016/j.jacc.2024.02.020

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).

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How to cite

APA:

Marton, A., Saffari, S.E., Rauh, M., Sun, R.N., Nagel, A.M., Linz, P.,... Titze, J. (2024). Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure. Journal of the American College of Cardiology, 83(15), 1386-1398. https://doi.org/10.1016/j.jacc.2024.02.020

MLA:

Marton, Adriana, et al. "Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure." Journal of the American College of Cardiology 83.15 (2024): 1386-1398.

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