Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

Abstract

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a new treatment strategy for heart failure with reduced ejection fraction (HFrEF) and—depending on the wistfully awaited results of two clinical trials (DELIVER and EMPEROR-Preserved)—may be the first drug class to improve cardiovascular outcomes in patients suffering from heart failure with preserved ejection fraction (HFpEF). Proposed mechanisms of action of this class of drugs are diverse and include metabolic and hemodynamic effects as well as effects on inflammation, neurohumoral activation, and intracellular ion homeostasis. In this review we focus on the growing body of evidence for SGLT2i-mediated effects on cardiac intracellular Na+ as an upstream mechanism. Therefore, we will first give a short overview of physiological cardiomyocyte Na+ handling and its deterioration in heart failure. On this basis we discuss the salutary effects of SGLT2i on Na+ homeostasis by influencing NHE1 activity, late INa as well as CaMKII activity. Finally, we highlight the potential relevance of these effects for systolic and diastolic dysfunction as well as arrhythmogenesis.

Potential Mechanisms of SGLT2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction

“…Finally, overall cytosolic Na + levels were also decreased by empagliflozin after 30 min and 24 h treatment in murine wildtype mice (Mustroph et al, 2018). Therefore, SGLT2i-dependent changes in myocardial Na + might constitute an important cardiac mechanism potentially also in HFpEF (Trum et al, 2021). In conclusion, studies in different experimental models reported an involvement of SGLT2i in cellular Ca 2+ and Na + homeostasis.…”

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

“…Physiologically, NCX mainly removes calcium from the intra- to the extracellular space, except in the early phase of action potential when, independent of the [Na + ] and [Ca 2+ ] transmembrane gradient, NCX transports Ca 2+ in the reverse direction into the cytosol. NCLX is mainly responsible for mitochondrial Ca 2+ release into the cytosol [ 139 ].…”

“…Hyperexpression of SGLT1 transporter mRNA or protein could also contribute to sodium overload, whose presence has repeatedly been confirmed in healthy hearts instead of SGLT2. Reduced capacity of Na + extrusion from the cytosol, a debated process mediated by the Na + /K + ATPase, may also contribute [ 139 , 148 ].…”

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…Moreover, empagliflozin has been shown to modulate Ca 2+ handling by lowering cytosolic Na + and Ca 2+ through inhibition of the Na + /H + (NHE1) exchanger and the Ca 2+ L-type channel and SERCA2a, combined with modulation of electrophysiological APD and QT interval shortening [146][147][148]. The salutary effects of SGLT2i on Na + homeostasis by influencing NHE1 activity, and the late INa and calcium/calmodulin-dependent kinase II (CaMKII) activity have been comprehensively discussed [149].…”