Analysis of the cardiac effects of sodium-glucose co-transporter 2 inhibitors in animals without diabetes and a clinical perspective

Emerging evidence points to a positive impact of sodium glucose co-transporter 2 (SGLT-2) inhibitors on cardiac structure and function, acutely (as early as 15 days) and chronically (up to 2 years). Accordingly, data from clinical studies appear to support the beneficial effects of this class of drugs on the cardiovascular system. However, the extent to which such effects may directly and/or indirectly be responsible for the beneficial actions of this class of drugs remains unclear. Based on the data in the literature, the actions of SGLT-2 inhibitors on the cardiac tissue in the absence of SGLT-2 co-transporter sites would suggest possible direct effects on calcium/ calmodulin-dependent kinase II (CaMKII), voltage-gated, Nav1.5 channels and sodium-calcium exchanger 1 (NCX1), Na+/H+ exchanger (NHX), the late INa associated with calcium transient, the rapid (IKr) and slow (IKs) delayed rectifier K+ currents, phosphorylated levels of myofilament regulatory proteins, xanthine oxidase ac-tivity and sarco(endo)plasmic reticulum calcium ATPase and/or intracellular, and/or possible genomic sites in the cardiac myocytes. Collectively, the experimental and clinical evidence as to the effects of SGLT-2 inhibitors on cardiac and vascular tissues appear multifaceted in nature with no consensus for definitive site(s) of actions. It is clear that further investigations both in animals and humans, in vitro and in vivo are needed to shed more light on the true nature of the pharmacological actions of this class of compounds, and the extent of their beneficial effects as reported in a population with heart failure.