OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2-4), end of treatment (ET) (days 12-14), and follow-up (FU) (days 15-18). RESULTS: Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150  mmol/24-h) did not significantly change during treatment (change at ST: 27.0 mmol/24-h [95% CI 222.4, 8.4]; change at ET: 2.1 mmol/24-h [228.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (26.1 mmHg [29.1, 23.1]; P<0.001) and ET (27.2 mmHg [210.0, 24.3]; P<0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (20.7 L [21.3, 20.1]; P50.02).Asexpected,24-hurinaryglucoseexcretionsignificantlyincreasedduring dapagliflozin treatment and reversed during FU. CONCLUSIONS: During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure-lowering effects.