Sodium-glucose-cotransporter 2 (SGLT2) inhibitors were originally developed to ameliorate diabetic status, but were soon found to exert beneficial effects on the kidney as well as the heart in both heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF respectively). These beneficial effects on HFpEF and HFrEF occurred independent of diabetic status, and the underlying mechanisms are slowly being unraveled. These mechanisms involve both effects on the kidney and the heart. In the kidney, SGLT2 inhibition inhibits the complex of SGLT2 and the Na-H exchanger (NHE), thereby improving natriuresis and renal perfusion, and reducing activity of the sympathetic nervous system, resulting in a slight reduction in blood pressure.1 
Cardiac benefits of SGLT2 inhibition include improved cardiac remodeling, reduced oxidative stress, an anti-inflammatory effect resulting in reduced interstitial fibrosis, and altered mitochondrial function.2, 3 Also, a beneficial effect of SGLT2 inhibition on the microvasculature has been shown, with improved endothelial function, increased NO production, reduced oxidative stress associated with reduced expression of inflammatory molecules ICAM and VCAM and reduced senescence.4

More recent studies suggest that increases in SGLT2 expression in the heart and vasculature occur in disease and are associated with increases in inflammatory conditions and oxidative stress. 
In a recent paper in Cardiovascular Research,5 Mroueh and colleagues investigated the relation between SGLT2 expression, oxidative stress and balance between NO and ROS in human samples of aorta and left ventricle obtained during cardiac surgery. They show that SGLT2 expression in the aorta is strongly correlated with activation of the renin angiotensin system (AT1R and ACE -expression), expression of inflammatory markers (IL-1β, IL-6, TNFα, ICAM, VCAM) and reduced expression of eNOS.  Presence of SGLT2 was observed in the endothelium of the thoracic aorta and in the coronary microcirculation as well as in cardiomyocytes. 
Higher expression of SGLT2was associated with increased oxidative stress, that could be inhibited by SGLT2 inhibition, inhibition of the renin-angiotensin system as well as inhibition of NADPH-oxidases (NOX). Consistent with a causal relation between inflammation, oxidative stress and SGLT2 inhibition, it was shown that exposure of porcine coronary endothelial cells to TNFα resulted in an increase in SGLT2 expression, which was mediated via activation of NF-κB and MAPkinases, suggesting a vicious cycle of inflammation, oxidative stress and SGLT2.

Inflammation and oxidative stress are not only involved in heart failure, but also key components of coronary microvascular dysfunction and INOCA. Although SGLT2 inhibition showed to improve peripheral endothelial function, and preclinical studies have shown a benefit of SGLT2 inhibition on coronary microvascular function and improved coronary flow reserve, studies on the effect of SGLT2 inhibition on coronary flow reserve have been ambiguous, with either no 6 or only small beneficial effects7, 8 at best.4 
With the study of Mroueh and co-workers5 in mind, perhaps patient stratification based on inflammation and oxidative stress in trials investigating SGLT2 inhibitor in INOCA would help to identify subgroups that might benefit from this treatment.