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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., Saffari, S.E., Rauh, M., Sun, R.N., Nagel, A.M., Linz, P., Lim, T.T., Takase-Minegishi, K., Pajarillaga, A., Saw, S., Morisawa, N., Yam, W.K., Minegishi, S., Totman, J.J., Teo, S., Teo, L.L.Y., Ng, C.T., Kitada, K., Wild, J., Kovalik, J.P., Luft, F.C., Greasley, P.J., Chin, C.W.L., 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 |
| ISSN: | 0735-1097 |
| Publisher: | Elsevier |
| Volume: | 83 |
| Number: | 15 |
| Page Range: | 1386-1398 |
| Date: | 16 April 2024 |
| Additional Information: | Erratum in: J Am Coll Cardiol 83(25):1386 |
| Official Publication: | https://doi.org/10.1016/j.jacc.2024.02.020 |
| PubMed: | View item in PubMed |
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