Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

Abstract

<b>Background: </b> <p>Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce 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. </p> <p><b>Methods: </b></p> <p>DAPASALT (NCT03152084) was a mechanistic, non-randomized, 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-hour blood pressure, and extracellular, intracellular and plasma volumes at start of treatment (ST; days 2-4), end of treatment (ET; days_12-14) and at follow-up (FU; days_15-18). </p> <p><b>Results:</b> </p> <p>Fourteen patients were included in the efficacy analysis. Mean [SD] baseline sodium excretion (150 [32] mmol/24-hours), did not significantly change during treatment (change at ST: -7.0 mmol/24-hours [95%CI: -22.4, 8.4]; change at ET 2.1 mmol/24-hours [95%CI: -28.8, 33.0]). Mean (SD) baseline 24-hour systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (-6.1 mmHg [95%CI: -9.1, -3.1]; p<0.001) and ET (-7.2 mmHg [95%CI: -10.0, -4.3]; p<0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (-0.7 L [95%CI: -1.3, 0.1]; p=0.02). As expected, 24-hour urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. </p> <p><b>Conclusions:</b></p> <p>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. </p>

A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

“…It is therefore possible that changes in sodium excretion could be attributed to changes in sodium intake rather than SGLT2 inhibition. A recent study in patients with T2D and preserved kidney function who adhered to a strict standardized sodium diet showed that the SGLT2 inhibitor dapagliflozin significantly decreased 24 h blood pressure without obvious changes in sodium excretion (Scholtes et al, 2021). This study suggests that other factors may contribute to the blood pressure-lowering effects of SGLT2 inhibitors.…”

The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure

“…Data showing inhibition of lithium reabsorption, as a marker for proximal tubular function, support this notion. 31 However, studies of proximal tubular sodium absorption have not been conducted in people with HF. Initial natriuresis is thought to contribute to the osmotic diuresis, which drives the increased urine output associated with acute SGLT2 inhibition, as shown in some 32,33 but not all studies.…”

“…Initial natriuresis is thought to contribute to the osmotic diuresis, which drives the increased urine output associated with acute SGLT2 inhibition, as shown in some 32,33 but not all studies. 31 The placebo-controlled RECEDE-CHF trial conducted in patients with T2D and HF demonstrated a significant increase in 24-hour urine volume without an increase in urinary sodium concentration when empagliflozin was used in combination with a loop diuretic. 34 Although RECEDE-CHF did not find a significant increase in the fractional excretion of sodium with empagliflozin, another study did, 32 a difference possibly explainable by the different time points studied between the 2 studies as well as differences in sodium intake at baseline.…”

“…The DAPASALT study, by contrast, was conducted in patients (N = 17) with T2D and preserved kidney function on a fixed sodium diet. 31 The study participants received dapagliflozin and had 24-hour urine collected prior to treatment, after acute dosing, after 2 weeks of treatment, and 3 days after treatment cessation, but changes in natriuresis or plasma volume were not found. 31 Whereas the bulk of sodium is reabsorbed in the proximal tubule, it is unclear to what extent SGLT2 transporters contribute to total sodium reabsorption in absolute terms.…”

“…31 The study participants received dapagliflozin and had 24-hour urine collected prior to treatment, after acute dosing, after 2 weeks of treatment, and 3 days after treatment cessation, but changes in natriuresis or plasma volume were not found. 31 Whereas the bulk of sodium is reabsorbed in the proximal tubule, it is unclear to what extent SGLT2 transporters contribute to total sodium reabsorption in absolute terms. This phenomenon may be particularly relevant in people with T2D, in whom there is increased glucose flux through the SGLT2 transporters owing to chronic tubular hyperglycemia.…”