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

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 (11) 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).