SGLT2 inhibitors: reviving the sodium-hydrogen exchanger cardioprotection hypothesis?
Abstract
This editorial refers to ‘Delayed ischaemic contracture onset by empagliflozin associates with NHE1 inhibition and is dependent on insulin in isolated mouse hearts’, by L. Uthman et al., pp. 1533–1545. The sodium-glucose linked transporter-2 (SGLT2) inhibitors, targeted to improve glycaemic control by attenuating renal glucose re-uptake, are emerging to be one of the most impactful cardiovascular drug classes of recent times. With clear and rapid-onset benefit upon cardiovascular outcomes, particularly in respect to heart failure rehospitalization,1 SGLT2 inhibitors are rapidly becoming an essential part of the Cardiologist’s pharmacopoeia. Remarkably, the mechanisms belying the cardioprotective effects of SGLT2 inhibitors remain obscure. Understanding the mechanisms behind their benefits is not a purely academic exercise: identifying how they influence the cardiovascular system will not only improve our understanding of the pathophysiology of cardiovascular disease, but also potentially enable re-purposing of these drugs beyond their current indications in patients with Type 2 diabetes mellitus. There has been much speculation as to the mechanisms of SGLT2 inhibitor-mediated cardioprotection, with many hypotheses being proffered.2 One such mechanism is through an off-target effect upon the sodium-hydrogen exchanger (NHE).3 A plasma membrane-bound antiporter, NHE plays vital role in maintaining intracellular pH and ion homeostasis under physiological conditions.4 However,…
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