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Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential. At present, whereas the SGLT2 inhibitors are widely applied in current clinical practice as an effective and well-tolerated treatment that increases the urinary excretion of glucose, less is known about the use of SGLT1 inhibitors. SGLT1s are of primary importance in the small intestine, an organ that does not express SGLT2, while in the kidney they are expressed in the late renal proximal tubules, where it reabsorbs the glucose escaped from the upstream SGLT2. Hence, SGLT1-mediated glucose reabsorption in the kidney is increased when the tubular glucose load overwhelms the capacity of SGLT2 or when the latter is inhibited. The role of SGLT1 in intestinal and renal glucose transport makes the transporter a potential target for antidiabetic therapy. Here, we briefly report the evidence on LX2761, a new inhibitor against SGLT1 and SGLT2 in vitro, which acts in vivo as a selective inhibitor of SGLT1 in the gastrointestinal tract. LX2761 improves glycemic control without the glycosuria-related side effects of SGLT2 inhibitors, particularly genitourinary tract infections. However, whether it represents a valid therapeutic option for all patients with diabetes or is more appropriate for specific phenotypes, e.g., patients with concomitant diabetes and chronic kidney disease, who may benefit less from the renal mechanism of selective SGLT2 inhibitors, remains to be tested in large randomized controlled trials.

SGLT1 and SGLT1 Inhibitors: A Role to Be Assessed in the Current Clinical Practice