Sodium-glucose cotransporter-2 inhibitors and sepsis: a story with two tails or with one tail?

Sepsis is a heterogeneous clinical syndrome characterized by dysregulated host response to infection. The pathophysiology of sepsis is very complex and it is now considered that sepsis has a variety of subtypes. During sepsis, apart from immune dysfunction, simultaneous activation of the complement and coagulation systems occur. These alterations damage the endothelium, cause microcirculatory dysfunction and decreased perfusion to tissues resulting in hypoxic damage causing vicious cycle in sepsis.Sodium-glucose cotransporter inhibitors (SGLTi) are a class of medications initially developed as glucose-lowering agents that have since been proven to have profound effects for kidney and heart protection in broad populations with or without diabetes. Especially SGLT2i, but also the combination of SGLT1/2i, have cardiovascular and renal benefits, independent of their glucose lowering effects. Interestingly, recent experimental studies have shown that SGLT2i have favorable effects during sepsis by modulation of immune system, improving tissue perfusion and hemodynamics. Clinical studies have shown that SGLT2i decreased sepsis severity and hospitalizations during sepsis. Apart from above mentioned effects, SGLT2i potentially modify gut microbiota, energetics and mitochondrial function which are involved in the pathogenesis of sepsis. In this review, we have summarized the experimental and clinical studies regarding the use of SGLT2i in sepsis and described potential mechanisms underlying these beneficial effects.