TY - JOUR
T1 - Empagliflozin in Heart Failure
T2 - Regional Nephron Sodium Handling Effects
AU - Rao, Veena S.
AU - Ivey-Miranda, Juan B.
AU - Cox, Zachary L.
AU - Moreno-Villagomez, Julieta
AU - Maulion, Christopher
AU - Bellumkonda, Lavanya
AU - Chang, John
AU - Field, M. Paul
AU - Wiederin, Daniel R.
AU - Butler, Javed
AU - Collins, Sean P.
AU - Turner, Jeffrey M.
AU - Wilson, F. Perry
AU - Inzucchi, Silvio E.
AU - Wilcox, Christopher S.
AU - Ellison, David H.
AU - Testani, Jeffrey M.
N1 - Publisher Copyright:
Copyright © 2023 by the American Society of Nephrology.
PY - 2024/2/1
Y1 - 2024/2/1
N2 - Significance StatementThe 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.BackgroundThe effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits.MethodsThis 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.ResultsEmpagliflozin 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.ConclusionsEmpagliflozin 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.
AB - Significance StatementThe 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.BackgroundThe effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits.MethodsThis 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.ResultsEmpagliflozin 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.ConclusionsEmpagliflozin 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.
KW - chronic heart failure
KW - diabetes mellitus
KW - diuretics
KW - heart failure
KW - SGLT2
KW - sodium (Na) transport
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U2 - 10.1681/ASN.0000000000000269
DO - 10.1681/ASN.0000000000000269
M3 - Article
C2 - 38073038
AN - SCOPUS:85184006855
SN - 1046-6673
VL - 35
SP - 189
EP - 201
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 2
ER -