Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects
Veena S. Rao, Juan B. Ivey-Miranda, Zachary L. Cox, Julieta Moreno-Villagomez, Christopher Maulion, Lavanya Bellumkonda, John Chang, M. Paul Field, Daniel R. Wiederin, Javed Butler, Sean P. Collins, Jeffrey M. Turner, F. Perry Wilson, Silvio E Inzucchi, Christopher S. Wilcox, David H. Ellison, Jeffrey M. Testani- Nephrology
- General Medicine
Background:
The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans but may be important for the cardio-renal benefits.
Methods:
The study utilized a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the proximal tubule (PT), loop of Henle (Loop), and distal nephron were 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 ∼40 grams 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 SGLT2 did not attenuate over 14 days of empagliflozin (p=0.14).) However, there were significant reductions in FELi (p=0.009), FENa (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.
Conclusion:
Empagliflozin caused substantial redistribution of intra-renal 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.