Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey

Abstract

Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, and inflammation, with underlying mechanisms including endothelial dysfunction, inflammation, oxidative stress, and metabolic alterations. Cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors observed in diabetic and non-diabetic patients are also related to their cardiac-specific, SGLT-independent mechanisms, in addition to the metabolic and hemodynamic effects. In search of the possible underlying mechanisms, a research campaign has been launched proposing varied mechanisms of action that include intracellular ion homeostasis, autophagy, cell death, and inflammatory processes. Moreover, the research focus was widened toward cellular targets other than cardiomyocytes. At the moment, intracellular sodium level reduction is the most explored mechanism of direct cardiac effects of SGLT2 inhibitors that mediate the benefits in heart failure in addition to glucose excretion and diuresis. The restoration of cardiac Na+ levels with consequent positive effects on Ca2+ handling can directly translate into improved contractility and relaxation of cardiomyocytes and have antiarrhythmic effects. In this review, we summarize clinical trials, studies on human cells, and animal models, that provide a vast array of data in support of repurposing this class of antidiabetic drugs.

Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats

“…Currently, several molecular and cellular mechanisms by which SGLT2-i protects the CV system have been identified ( 47 – 49 ). The reduction of oxidative stress is considered a potential mechanism for the suppression of cardiac remodeling by SGLT2-i, by balancing abnormal Na + and Ca 2+ levels and protecting mitochondrial function ( 48 ).…”

Pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction

“…Later, it was found that dapagliflozin and canagliflozin inhibited Na + /H + exchanger activity and reduced cytosolic Na + [ 73 ]. Additionally, empagliflozin reduced Ca 2+ /calmodulin-dependent kinase II (CaMKII) activity and CaMKII-dependent sarcoplasmic reticulum Ca 2+ leak [ 74 , 75 ].…”

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

“…The protective effects of SGLT2is against the cardiovascular (CV) and renal complications of T2DM appear to be independent of their glucose-lowering activity, with particular value being demonstrated in the reduction of risk regarding hospitalisation for heart failure (HHF) and progression of diabetic kidney disease (DKD) as well as lowering the incidence of major adverse cardiovascular events (MACE) [ 4 – 36 ]. Recently published reviews have described and explored the putative mechanisms underlying the cardiorenal benefits of SGLT2is, emphasising the direct and indirect effects that these medicines have on pathways that mediate inflammation, oxidative stress and endothelial cell dysfunction [ 37 , 38 ].…”