Sodium-glucose Cotransporter 2 Inhibitors: The Pleiotropic Mechanisms of Actions.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a new class of oral antidiabetic drugs. So far, there are three agents approved for use in Europe and in the USA, two in Japan and another four agents under testing. OBJECTIVE: The purpose of this study is to describe the mechanism of action and the favorable and adverse effects of SGLT-2 inhibitors. METHOD: A thorough review of literature indexed in PubMed, Scopus and Cochrane databases were conducted. Original papers, review papers and their relevant references in English, from 2005 to February 2017, were included. RESULTS: The main mechanism of action is the glycosuria induced by the inhibition of SGLT-2, located in the early segment of the proximal convoluted tubule. Along with large amounts of glucose, sodium, water and uric acid are also excessively excreted in urine. These actions have various, both desired and adverse, consequent implications in kidneys, blood pressure, cardiovascular system and other systems. Moreover, SGLT-2 inhibitors act directly to organs other than the kidneys, as SGLT-2 can be expressed there. CONCLUSION: The underlying mechanisms responsible for the SGLT-2 inhibitor actions, are pleiotropic and occur in the kidneys, as well as in other target organs. The comprehension of these mechanisms, not only permits us to understand their actions better, but it could also help us to predict more of their undisclosed favorable actions, as well as their rare adverse effects.