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.

Keywords: Cardiac function; Inflammation; Ion homeostasis; Metabolism; Oxidative stress; Sodium-glucose-cotransporter 2 inhibitors.

Fig. 1

Search strategy and literature obtained. A Full search strategy with all search terms. B articles obtained and excluded. A total of 70 studies were initially retrieved from electronic databases using the search terms. There were 69 studies remaining after exclusion of duplicates using EndNote X9. There were 29 studies excluded because they did not study direct cardiac effects or applied overdoses of SGLT2i or contained not original research. In total we include 40 articles

Fig. 2

SGLT2i and the Sodium-interactome of cardiac cells. Stress conditions will activate the sodium/hydrogen exchanger (NHE) and/or sodium channel (Nav1.5) and/or induce expression of SGLT2 in the plasma membrane facilitating increases in cytosolic sodium ([Na⁺]_I. Increases in ([Na⁺]_I can result in increased calcium ([Ca²⁺]_I through impairment of NCX. ([Na⁺]_I will transfer into mitochondria through the sodium/calcium exchanger (NCLX) in the mitochondrial membrane, increasing mitochondrial Na⁺ and decreasing mitochondrial Ca²⁺. Decreased mitochondrial Ca²⁺ shifts metabolism away from fatty acid oxidation (FAO) towards glucose oxidation (GO) and facilitates ROS production through diminished anti-oxidant activity of ROS detoxifying enzyme systems. Increased mitochondrial Na⁺ can increase mitochondrial ROS through decreases in membrane fluidity. Increased cytosolic Ca²⁺ stimulates hypertrophy through calcineurin activation, cytosolic ROS production through activation of NADPH oxidase, and inflammation through activation of the Nlrp3 inflammasome. Oxidative stress and inflammation causes cardiac dysfunction and positively feed backs to the NHE and Nav1.5 by activating these channels