SGLT2 inhibitors in translational medicine: A paradigm shift for diabetes and heart health

Abstract

Diabetes mellitus (DM) is a major contributor to a number of catastrophic health disorders, including heart attacks, strokes, kidney failure, blindness, and lower limb amputations. In 2023, DM was recognized by the World Health Organization (WHO) as a major cause of death. Diabetes is becoming more and more common, and any family member could be impacted. Due to the limited availability of current antidiabetic drugs, the urgent need for new active pharmaceutical ingredients becomes clear. In recent decades, sodium-glucose cotransporter-2 (SGLT2) has drawn interest as a key target for type 2 diabetes treatment. This is attributed to its innovative mechanism of action, which works independently of the insulin signalling pathway. Gliflozines, which mainly function as SGLT2 inhibitors, are a significant class of drugs used to treat type II diabetes. Several gliflozines have received approval from regulatory bodies like the FDA, EMA, and PMDA, and other compounds are presently undergoing advanced research and development. Phlorizin, a naturally occurring O-glucoside, serves as a starting compound from which various derivatives have been synthesized, including O-glucoside, C-glucoside, and N-glucoside derivatives. In addition to providing insights into the chemical modifications that increase the potency of SGLT2 inhibitors and their analogues, the review emphasizes the structure-activity relationship of these drugs. The collaborative efforts of researchers in the ongoing synthesis and development of SGLT2 inhibitors, as well as the progress achieved in the field so far, are also highlighted.