A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena

Abstract

Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug, the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors (SGLT2i) showed efficacy in decreasing overall mortality, hospitalization, and sudden death in patients of this very population, in whom chronic or acute ischemia count among the first cause. Remarkably, this benefit was observed independently from diabetic status, and benefited both preserved and altered ventricular ejection fraction. This feature, observed in several large randomized controlled trials, suggests additional effects from SGLT2i beyond isolated glycemia control. Indeed, both in-vitro and animal models suggest that inhibiting the Na⁺/H⁺ exchanger (NHE) may be key to preventing ischemia/ reperfusion injuries, and by extension may hold a similar role in ischemic damage control and ischemic preconditioning. Yet, several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules. Because of a large therapeutic margin with few adverse events, ease of prescription and potential pharmacological efficacity, SGLT2i could be candidate for wider indications. In this review, we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation, by first listing known mechanisms, including metabolic switch, prevention of lethal arrythmias and others, which portend the latter, and second, hypothesize how the former may interact with these mechanisms.

Keywords: SGLT2 inhibitors, Ischemia-reperfusion injuries, Sodium-proton exchanger, Myocardial ischemia, Immunomodulation

Core Tip: The antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors (SGLT2i) showed efficacy in decreasing mortality in patients with chronic heart failure, in whom ischemia counts among the first cause. Remarkably, this benefit was observed independently from diabetic status. This feature, yielded from several randomized controlled trials, suggests additional effects from SGLT2i beyond isolated glycemia control. Indeed, previous in-vitro and animal models analyzed altogether suggests the role of the inhibition of the Na⁺/H⁺ exchanger, which holds a pivotal role in ischemia/reperfusion injuries. In this review, we aim to summarize evidence which associate SGLT2i and ischemia/reperfusion injuries, by first listing known mechanisms which portend the latter, and second, hypothesize how the former may interact with these mechanisms.