Sizing SGLT2 Inhibitors Up: From a Molecular to a Morpho-Functional Point of View

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, have recently been shown to reduce cardiovascular death and hospitalization in patients with heart failure, representing a revolutionary therapeutic tool. The purpose of this review is to explore their multifaceted mechanisms of actions, beyond their known glucose reduction power. The cardioprotective effects of gliflozins seem to be linked to the maintenance of cellular homeostasis and to an action on the main metabolic pathways. They improve the oxygen supply for cardiomyocytes with a considerable impact on both functional and morphological myocardial aspects. Moreover, multiple molecular actions of SGLT2i are being discovered, such as the reduction of both inflammation, oxidative stress and cellular apoptosis, all responsible for myocardial damage. Various studies showed controversial results concerning the role of SGLT2i in reverse cardiac remodeling and the lowering of natriuretic peptides, suggesting that their overall effect has yet to be fully understood. In addition to this, advanced imaging studies evaluating the effect on all four cardiac chambers are lacking. Further studies will be needed to better understand the real impact of their administration, their use in daily practice and how they can contribute to benefits in terms of reverse cardiac remodeling.