SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models

Abstract

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of effective drugs managing patients, who suffer from type 2 diabetes (T2D): Landmark clinical trials including EMPA-REG, CANVAS and Declare-TIMI have demonstrated that SGLT2 inhibitors reduce cardiovascular mortality and re-hospitalization for heart failure (HF) in patients with T2D. It is well established that there is a strong independent relationship among infarct size measured within 1 month after reperfusion and allcause death and hospitalization for HF: The fact that cardiovascular mortality was significantly reduced with the SGLT2 inhibitors, fuels the assumption that this class of therapies may attenuate myocardial ischaemic injury. Experimental evidence demonstrates that SGLT2 inhibitors exert cardioprotective effects in animal models of acute myocardial infarction through improved function during the ischemic episode, reduction of infarct size and a subsequent attenuation of heart failure development. The aim of the present review is to outline the current state of preclinical research in terms of myocardial ischemia/reperfusion injury (I/R) and infarct size for clinically available SGLT2 inhibitors and summarize some of the proposed mechanisms of action that may contribute to the unexpected beneficial cardiovascular effects of this class of compounds.

Sodium–glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes

“…The tubule-centered hypothesis [52] asserts that tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis; by attenuating the proximal reabsorption of sodium and glucose, SGLT-2i mitigate hyperfiltration and normalize tubule-glomerular feedback signals. Moreover, the list of their cardiorenal protective effects is expanding and includes, among others, preventing adverse cardiac remodeling and ischemia/ reperfusion injury, increasing circulating hematopoietic progenitor cells, decreasing epicardial fat mass, decreasing oxidative stress and inflammation, increasing erythropoietin levels and inhibiting the sympathetic nervous system [53,54].…”

Bibliometric Study of Sodium Glucose Cotransporter 2 Inhibitors in Cardiovascular Research

“…Conversely, numerous studies in preclinical models have been conducted to confirm the CV benefits of SGLT2 inhibitors, including reducing infarct size in reperfused ischemic hearts (Andreadou et al, 2020), attenuating cardiac fibrosis (Lee et al, 2019) and coronary microvascular dysfunction (Adingupu et al, 2019), reducing cardiac inflammation (Byrne et al, 2020), ameliorating adverse ventricular remodeling by affecting cardiac metabolism (Santos-Gallego et al, 2019;Yurista et al, 2019), and improving cardiac function. However, the precise molecular mechanisms underlying those processes remain unclear.…”

Empagliflozin Decreases Lactate Generation in an NHE-1 Dependent Fashion and Increases α-Ketoglutarate Synthesis From Palmitate in Type II Diabetic Mouse Hearts

“…Therefore, as a secondary goal, we examined whether possible SGLT2i effects on cardiac glucose metabolism are mediated through NHE-1 inhibition, by also studying SGLT2i effects in the presence of an NHE-1 inhibitor. Finally, effects of SGLT2i on survival proteins reported to facilitate cardioprotection against ischemic insult (15), and occasionally reported to be affected by SGLT2i's in isolated cells or in the in vivo condition (e.g., STAT3, AMPK, Akt, eNOS) (16), were also examined for the isolated heart. Therefore, in the present study we hypothesized that the SGLT2i Empagliflozin (EMPA) affects glucose and fatty acid metabolism in the isolated diabetic mouse heart, with possible involvement of cardiac NHE and/or of survival proteins.…”