@article{b82edb4866c5404a877dfe5c04486449,
title = "Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects",
abstract = "Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute a promising drug treatment for heart failure patients with either preserved or reduced ejection fraction. Whereas SGLT2i were originally developed to target SGLT2 in the kidney to facilitate glucosuria in diabetic patients, it is becoming increasingly clear that these drugs also have important effects outside of the kidney. In this review we summarize the literature on cardiac effects of SGLT2i, focussing on pro-inflammatory and oxidative stress processes, ion transport mechanisms controlling sodium and calcium homeostasis and metabolic/mitochondrial pathways. These mechanisms are particularly important as disturbances in these pathways result in endothelial dysfunction, diastolic dysfunction, cardiac stiffness, and cardiac arrhythmias that together contribute to heart failure. We review the findings that support the concept that SGLT2i directly and beneficially interfere with inflammation, oxidative stress, ionic homeostasis, and metabolism within the cardiac cell. However, given the very low levels of SGLT2 in cardiac cells, the evidence suggests that SGLT2-independent effects of this class of drugs likely occurs via off-target effects in the myocardium. Thus, while there is still much to be understood about the various factors which determine how SGLT2i affect cardiac cells, much of the research clearly demonstrates that direct cardiac effects of these SGLT2i exist, albeit mediated via SGLT2-independent pathways, and these pathways may play a role in explaining the beneficial effects of SGLT2 inhibitors in heart failure.",
keywords = "Arrhythmia, Heart failure, Inflammation, Oxidative stress, SGLT2, Sodium, Stiffness",
author = "Dyck, {Jason R. B.} and Samuel Sossalla and Nazha Hamdani and Ruben Coronel and Weber, {Nina C.} and Light, {Peter E.} and Zuurbier, {Coert J.}",
note = "Funding Information: JRBD, NH, RC, NCW, PEL: nothing to report. SS received speaker{\textquoteright}s/consultancy honoraria from Boehringer Ingelheim Pharma GmbH and AstraZeneca ; CJZ received grant support from Boehringer Ingelheim Pharma GmbH . Funding Information: JRBD is a Canada Research Chair in Molecular Medicine and receives funding from the Canadian Institutes of Health Research (CIHR). NH is supported by DFG HA 7512/2-4 ; SS is supported in part by the Else-Kr{\"o}ner-Fresenius Stiftung and the Deutsche Forschungsgemeinschaft via research grants ( 2017_A137 , and SO 1223/4-1 ); PEL holds the Dr Charles A. Allard Chair in Diabetes Research ; CJZ is supported by the European Foundation for the Study of Diabetes (EFSD). Funding Information: JRBD, NH, RC, NCW, PEL: nothing to report. SS received speaker's/consultancy honoraria from Boehringer Ingelheim Pharma GmbH and AstraZeneca; CJZ received grant support from Boehringer Ingelheim Pharma GmbH.JRBD is a Canada Research Chair in Molecular Medicine and receives funding from the Canadian Institutes of Health Research (CIHR). NH is supported by DFG HA 7512/2-4; SS is supported in part by the Else-Kr?ner-Fresenius Stiftung and the Deutsche Forschungsgemeinschaft via research grants (2017_A137, and SO 1223/4-1); PEL holds the Dr Charles A. Allard Chair in Diabetes Research; CJZ is supported by the European Foundation for the Study of Diabetes (EFSD). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jun,
day = "1",
doi = "https://doi.org/10.1016/j.yjmcc.2022.03.005",
language = "English",
volume = "167",
pages = "17--31",
journal = "Journal of molecular and cellular cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
}