Dual sodium-glucose cotransporter (SGLT) 1/2 versus pure SGLT2 inhibitors: two distinct drug categories or one class with multiple faces?

According to their selectivity for sodium-glucose cotransporters (SGLT) 1 and 2, gliflozins could be subdivided into two additional categories: pure SGLT2 inhibitors, which are highly selective for SGLT2, and dual SGLT1/2 inhibitors which, in addition to SGLT2, exhibit strong inhibitory activity for SGLT1.This article aims to discuss whether the pharmacological differences between the two subtypes of gliflozins could be translated into different efficacy and safety characteristics that might be important for clinical practice.In large cardiovascular outcome trials, dual inhibitors have shown a unique efficacy profile in terms of reducing glycemia in patients with severe renal impairment and decreasing the risk of atherosclerotic outcomes. These features do not characterize selective SGLT2 inhibitors and could be attributed to the parallel inhibition of SGLT1. The increased risk of diarrhea and severe hypoglycemia observed only with dual inhibitors is probably related to their action in the gut and brain, respectively. However, differences in populations included in various studies should be considered when attempting to translate their findings into clinical practice; therefore, head-to-head trials are needed to shed more light on this issue and provide clear guidance to clinicians.