Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects
Authors: Rao Veena S. , Ivey-Miranda Juan B. , Cox Zachary L. , Moreno-Villagomez Julieta , Maulion Christopher , Bellumkonda Lavanya , Chang John , Field M. Paul , Wiederin Daniel R. , Butler Javed , Collins Sean P. , Turner Jeffrey M. , Wilson F. Perry , Inzucchi Silvio E. , Wilcox Christopher S. , Ellison David H. , Testani Jeffrey M. 
Published: December 2023

Significance Statement
The effect of sodium–glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium–glucose cotransporter-2. This finding was not driven by an “osmotic diuretic” effect; however, several parameters changed in a manner consistent with inhibition of the sodium–hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling.

Background
The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits.

Methods
This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide.

Results
Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop (P < 0.001) and distal nephron (P < 0.001). Inhibition of sodium–glucose cotransporter-2 did not attenuate over 14 days of empagliflozin (P = 0.14). However, there were significant reductions in FELi (P = 0.009), fractional excretion of sodium (P = 0.004), and absolute fractional distal sodium reabsorption (P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT.

Conclusions
Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile.

Clinical Trial registry name and registration number
ClinicalTrials.gov (NCT03027960).