Pharmacological mechanisms and clinical applications between SGLT1 and SGLT2 inhibitors in type 2 diabetes and diabetic kidney disease: An analytic review

Sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), key members of the solute carrier (SLC) family, are pivotal for glucose reabsorption. Inhibitors targeting these transporters act by competitively occupying the glucose-binding site, effectively blocking glucose reabsorption and thereby lowering blood glucose levels. Clinical evidence indicates a gradual decline in the glycemic efficacy of gliflozin drugs following long-term administration, a phenomenon attributed to the compensatory upregulation of SGLT1-mediated reabsorption. Consequently, a comparative analysis of the pharmacological mechanisms underlying SGLT2 inhibitors (SGLT2i) and SGLT1 inhibitors (SGLT1i) is crucial for guiding optimal clinical therapy. This review begins by discussing the structure-function relationship of SGLT1 and SGLT2. It then focuses on currently approved gliflozins, elucidating the interaction mechanisms between these inhibitors and their targets (SGLT1 and SGLT2) based on structural insights, and further explores the implications of these mechanisms for clinical drug application.