Chapter 7 - SGLT2 Inhibitors for Type 2 Diabetes

Abstract

Publisher Summary This chapter summarizes the biological rationale, the clinical trials, and the preclinical research of sodium glucose cotransporter 2 (SGLT2) inhibitors. Type 2 diabetes mellitus is a progressive disease characterized by hyperglycemia, increased peripheral insulin resistance, and declining insulin secretion. Given the difficulty in achieving sufficient glycemic control for many diabetic patients using current therapies, there is an unmet medical need for new antidiabetic agents, especially insulin-independent therapies. Blocking glucose reabsorption in the kidney and lowering blood glucose levels through glucose excretion into the urine provide a novel insulin-independent therapy. Filtered plasma glucose is reabsorbed in the renal tubule mainly by SGLT2 and reenters the systemic circulation. Recent Phase II and Phase III clinical data of SGLT2 inhibitors and genetic studies of SGLT2 mutations in humans have provided strong evidence for SGLT2 as a promising new target for treating diabetes. This potential new therapy may be used as a monotherapy or in combination with existing therapies to achieve an additive effect in controlling blood glucose levels. Inhibition of renal glucose reabsorption by SGLT2 inhibitors and subsequent glucose excretion into urine is a unique mechanism of action to lower blood glucose levels. Recent clinical data demonstrate that this potential new insulin-independent antidiabetic therapy can not only reduce hemoglobin A1c (HbA1c) levels as effectively well as existing therapeutic agents but also confer other beneficial features, such as body weight loss and low propensity for causing hypoglycemia. Overall, the available data show that SGLT2 inhibitors have demonstrated good benefit-risk profiles in human clinical trials.