Direct cardiac effects of SGLT2 inhibitors

Abstract

Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) demonstrate large cardiovascular benefit in both diabetic and non-diabetic, acute and chronic heart failure patients. These inhibitors have on-target (SGLT2 inhibition in the kidney) and off-target effects that likely both contribute to the reported cardiovascular benefit. Here we review the literature on direct effects of SGLT2is on various cardiac cells and derive at an unifying working hypothesis. SGLT2is acutely and directly (1) inhibit cardiac sodium transporters and alter ion homeostasis, (2) reduce inflammation and oxidative stress, (3) influence metabolism, and (4) improve cardiac function. We postulate that cardiac benefit modulated by SGLT2i’s can be commonly attributed to their inhibition of sodium-loaders in the plasma membrane (NHE-1, Nav1.5, SGLT) affecting intracellular sodium-homeostasis (the sodium-interactome), thereby providing a unifying view on the various effects reported in separate studies. The SGLT2is effects are most apparent when cells or hearts are subjected to pathological conditions (reactive oxygen species, inflammation, acidosis, hypoxia, high saturated fatty acids, hypertension, hyperglycemia, and heart failure sympathetic stimulation) that are known to prime these plasmalemmal sodium-loaders. In conclusion, the cardiac sodium-interactome provides a unifying testable working hypothesis and a possible, at least partly, explanation to the clinical benefits of SGLT2is observed in the diseased patient.

Comparison of cardiovascular outcomes between SGLT2 inhibitors in diabetes mellitus

“…First, we analyzed patients with DM without a history of CVD in this study, and therefore, this study focuses on the cardiovascular outcomes in a primary prevention setting. Although the cardiovascular benefit of SGLT2 inhibitor use in primary prevention settings has been shown in various studies [ 20 , 23 , 24 ], it would be more evident in secondary prevention settings [ 8 , 25 ]. Therefore, further investigations, including patients with DM and a history of CVD, are warranted to compare the cardiovascular outcomes between SGLT2 inhibitors in secondary CVD prevention settings.…”

Targeting High Glucose-Induced Epigenetic Modifications at Cardiac Levels: The Role of SGLT2 and SGLT2 Inhibitors

“…Previous studies clearly demonstrated that SGLT2i effects at cardiac level are mediated through the modulations of SGLT1, Na+/H + exchanger 1 (NHE1), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and late Na + current (late INa) [35]. Indeed, we recently provided evidences that SGLT2 protein is expressed in human hearts of diabetic and non-diabetic patients and in human cardiomyocyte and that hyperglycemia condition induces its overexpression.…”

Effect of Metformin on T2D-Induced MAM Ca2+ Uncoupling and Contractile Dysfunction in an Early Mouse Model of Diabetic HFpEF

“…In parallel, several studies suggested a potential competitive effect of metformin with HF treatments [ 33 ], including sulphonylureas [ 34 ] and SGLT2i in the CANVAS [ 35 ] and EMPA-REG OUTCOME trials [ 36 ]. Recent investigations are now suggesting a direct cardiac effect of gliflozins [ 37 , 38 ]. Further mechanistic studies are therefore required to determine if SGLT2i improves the cardiac function by preserving the MAM Ca 2+ coupling in models of diabetic HFpEF, and whether metformin could interfere with the protective effect of SGLT2i.…”