Journal Logo


Heart and Sodium–Glucose Cotransporter 2 Inhibitors: A Sodium Dilemma

Oyesomi, Elizabeth T. MD; Tabrizchi, Reza PhD

Author Information
Journal of Cardiovascular Pharmacology: May 2022 - Volume 79 - Issue 5 - p 641-643
doi: 10.1097/FJC.0000000000001229
  • Free

There has been accumulating evidence in the peer-reviewed literature over the past 5 years that sodium–glucose cotransporter 2 (SGLT-2) inhibitors (eg, empagliflozin and dapagliflozin) offer health-associated benefits in patients with heart failure and diabetes.1,2 More recently, the American Heart Association included this class, namely empagliflozin and dapagliflozin, as adjunct therapy to the conventional group of drugs for the treatment of patients with heart failure without diabetes.2,3 The recommendations were made based on the data presented in some recent clinical trials.4 Although the use of this class of drugs produces significant clinical benefits to patients with heart failure without diabetes, the true nature of the mechanism(s) of action remains yet to be fully determined, both in experimental and clinical settings.

Among possible mechanisms for the action of this class of drugs (empagliflozin) was inhibition of the Na+–H+ exchanger in cardiac myocytes.5 This suggestion has become an interesting point of discussion. The original suggestion by Baartscheer et al5 was made using freshly isolated rat and rabbit cardiac tissues. The investigators from the same laboratory also reported that empagliflozin inhibited Na+–H+ exchanger in male isolated mouse (CI78B1/6NCr1) cardiac myocytes and also produced coronary vasodilation using the Langendorff perfused heart technique, while not being capable of affecting cardiac function (eg, dP/dt), cardiac energetics, or oxygen consumption.6 Subsequently, work by Chung et al7 reported that no inhibition of Na+–H+ exchanger occurred with empagliflozin in rat cardiac myocytes, and there was no vasodilation of coronary arteries or inhibition of left ventricular contraction using the perfused heart Langendorff technique. A further exchange of dialog in the peer-reviewed literature by investigators of the 2 laboratories still has not led to the resolution of the dichotomies in the outcomes.

Accordingly, this has put the 2 observations at a crossroad. Nonetheless, there are some differences in the methodology and experimental approach and the added matter of species differences. It seems that the experimental set-up in the laboratory of Baartscheer et al,5,6 where inhibition with empagliflozin has been effectively noted, uses moderate amounts of bicarbonate in the 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) solution, and the pH of the buffer is around 7.2 and perhaps subject to some modest oscillations. By contrast, Chung et al7 fixed the pH at 7.4 using HEPES with no bicarbonate in the salt solution. Thus, it is possible that the lower pH and bicarbonate ions may play a role in the final outcomes of the observations in each. An attempt by Zuurbier et al8 to replicate Chung et al's experimental approach showed that empagliflozin did lead to the retardation of intracellular Na+, but at pH 7.4, the inhibitory effect was at the lower end; in addition, rabbit isolated cardiac myocytes were used instead of rat cardiac myocytes, which were used by Chung et al7,9 in their studies. It is possible that the small concentration of bicarbonate in the HEPES buffer may have played a role in lowering the concentration of intracellular Na+. It is interesting to note that Grace et al10 had reported that the Na+–H+ exchanger and Na+ and bicarbonate-dependent mechanisms contributed approximately equally (about 50% each) to proton efflux at internal pH 6.9 during recovery from intracellular acidosis in the isolated ferret hearts. As the internal pH for the experiments described by Zuurbier et al8 reached values below 6.9, it is possible that in a circumstance where bicarbonate is present, the inhibitory effects of empagliflozin may become multifaceted and perhaps significant.

However, there is the issue of why empagliflozin did not produce negative inotropic effects in the perfused hearts like that of cariporide (a Na+–H+ exchanger inhibitor).6,7 There is evidence in the literature to indicate that inhibitors of the Na+–H+ exchanger in the isolated perfused working heart can diminish contractions.10,11 This means that if empagliflozin did inhibit Na+–H+ exchanger in the isolated cardiac myocyte cell preparations, the effect did not extend to the inhibition of the excitation–contraction process in the perfused working heart (ie, Langendorff technique).6,7

Nonetheless, there are also ample data to indicate that chronic treatment of animals with heart failure with Na+–H+ exchanger inhibitors leads to beneficial effects. Accordingly, several studies have reported that inhibition of Na+–H+ exchanger in rats and rabbits with myocardial infraction (left coronary artery ligation) leads to a reduction in cardiac hypertrophy and failure.12–15 Engelhardt et al16 have reported positive outcomes after Na+–H+ exchanger inhibition in the prevention of hypertrophy, fibrosis, and heart failure in β1-adrenoceptor transgenic mice. In addition, chronic inhibition of Na+–H+ exchanger in an experimental model (rabbit) of pressure/volume overload has provided outcomes of reduced hypertrophy, cellular remodeling, and retardation of failure.17,18

This highlights a number of dilemmas associated with this debate: (1) the discord in outcomes of the multiple studies involving the effects of empagliflozin on cardiac Na+–H+ exchanger and (2) how to interpret these findings in the context of the evidence of the beneficial effects of empagliflozin in patients with heart failure. First, because multiple species and conditions seem to have been used to describe the effects of empagliflozin in cardiac myocytes on Na+–H+ exchanger, it leaves us no closer to resolving the matter. Second, which is really at the center of this issue, is the lack of inhibitory effects of empagliflozin in contrast to that of cariporide (Na+–H+ exchanger inhibitor) in the isolated perfused heart preparations using the Langendorff technique. Third, there is the lack of evidence in an isolated failing heart preparation without diabetes. Therefore, this makes any suggestion as to the possible beneficial effects of empagliflozin in the heart, and associated with the inhibition of Na+–H+ exchanger, a challenging one.

In a recent report by Philippaert et al,19 it was found that empagliflozin was capable of inhibiting the late INa in a mouse model of heart failure, and this inhibitory action was not unique to the mentioned SGLT-2 inhibitor, but was shared with others namely dapagliflozin and canagliflozin. Moreover, empagliflozin was noted to prevent activation of nuclear-binding domain-like receptor 3 (NLRP3) inflammasome and retard the actions of late INa associated with calcium transients in isolated single myocytes. In addition, the presence of empagliflozin reduced the activation of NLRP3 inflammasome, while improving left ventricular excitation–contraction function, after ischemia in vitro.19 Although, in the latter studies, no functional data were presented as to the actions of empagliflozin in chronic failing hearts, the evidence seems to support positive effects of empagliflozin in modulating intracellular calcium by affecting Na+ flux. Accordingly, it will be helpful to determine the functional effects of empagliflozin and other SGLT-2 inhibitors in different models of heart failure in the absence of diabetes so to determine its pharmacological effects.

It should be noted that in a study, Trum et al20 reported that empagliflozin significantly impaired pHi recovery, from acidic condition (pHi ∼5.6), comparable with cariporide in the isolated human atrial cardiomyocyte cell preparations, leading to the suggestion of the inhibition of Na+–H+ exchanger in such tissue. However, it will be enlightening to determine whether parallel effects can be shown in human ventricular muscle and whether such effects are primarily due to the direct inhibition of Na+–H+ exchanger in a functioning ventricle.

Collectively, the current evidence seems to suggest that empagliflozin may be capable of affecting the concentration of intracellular Na+, but robust evidence that such an effect may produce beneficial cardiac effects in patients with heart failure without diabetes remains to be fully elucidated.


1. Chen C, Peng H, Li M, et al. Patients with type 2 diabetes mellitus and heart failure benefit more from sodium-glucose cotransporter 2 inhibitor: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;12:664533.
2. Writing Committee, Maddox TM, Januzzi JL Jr, Allen LA, et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2021;77:772–810.
3. Bozkurt B, Hershberger RE, Butler J, et al. 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical data standards (Writing committee to develop clinical data standards for heart failure). J Am Coll Cardiol. 2021;77:2053–2150.
4. Wingo MT, Huber JM, Szostek JH, et al. Update in outpatient general internal medicine: practice-changing evidence published in 2020. Am J Med. 2021;134:854–859.
5. Baartscheer A, Schumacher CA, Wüst RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60:568–573.
6. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia. 2018;61:722–726.
7. Chung YJ, Park KC, Tokar S, et al. Off-target effects of SGLT2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart. Cardiovasc Res. 2020;117:2794–2806.
8. Zuurbier CJ, Baartscheer A, Schumacher CA, et al. SGLT2 inhibitor empagliflozin inhibits the cardiac Na+/H+ exchanger 1: persistent inhibition under various experimental conditions. Cardiovasc Res. 2021;117:cvab129.
9. Chung YJ, Park KC, Tokar S, et al. SGLT2 inhibitors and the cardiac Na+/H+ exchanger-1: the plot thickens. Cardiovasc Res. 2021;117:2702–2704.
10. Grace AA, Kirschenlohr HL, Metcalfe JC, et al. Regulation of intracellular pH in the perfused heart by external HCO3- and Na+-H+ exchange. Am J Physiol. 1993;265:H289–H298.
11. Ten Hove M, Nederhoff MG, Van Echteld CJ. Relative contributions of Na+/H+ exchange and Na+/HCO3- cotransport to ischemic Nai+ overload in isolated rat hearts. Am J Physiol Heart Circ Physiol. 2005;288:H287–H292.
12. Yoshida H, Karmazyn M. Na+/H+ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium. Am J Physiol Heart Circ Physiol. 2000;278:H300–H304.
13. Kusumoto K, Haist JV, Karmazyn M. Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2001;280:H738–H745.
14. Chen L, Chen CX, Gan XT, et al. Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition. Am J Physiol Heart Circ Physiol. 2004;286:H381–H387.
15. Rungwerth K, Schindler U, Gerl M, et al. Inhibition of Na+-H+ exchange by cariporide reduces inflammation and heart failure in rabbits with myocardial infarction. Br J Pharmacol. 2004;142:1147–1154.
16. Engelhardt S, Hein L, Keller U, et al. Inhibition of Na+-H+ exchange prevents hypertrophy, fibrosis, and heart failure in beta1-adrenergic receptor transgenic mice. Circ Res. 2002;90:814–819.
17. Baartscheer A, Schumacher CA, van Borren MM, et al. Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res. 2005;65:83–92.
18. Baartscheer A, Hardziyenka M, Schumacher CA, et al. Chronic inhibition of the Na+/H+—exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. Br J Pharmacol. 2008;154:1266–1275.
19. Philippaert K, Kalyaanamoorthy S, Fatehi M, et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose cotransporter 2 inhibitor empagliflozin. Circulation. 2021;143:2188–2204.
20. Trum M, Riechel J, Lebek S, et al. Empagliflozin inhibits Na+/H+exchanger activity in human atrial cardiomyocytes. ESC Heart Fail. 2020;7:4429–4437.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.