Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus

Abstract

Although hyperglycemia is a key therapeutic focus in the management of patients with type 2 diabetes mellitus (T2DM), many patients experience sub-optimal glycemic control. Current glucose-lowering agents involve the targeting of various body organs. Sodium glucose co-transporter type 2 (SGLT2) inhibitors target the kidney, reduce renal glucose reabsorption, and increase urinary glucose elimination, thus lowering glucose blood levels. This review examines some of the key efficacy and safety data from clinical trials of the main SGLT2 inhibitors approved or currently in development, and provides a rationale for the use of SGLT2 inhibitors in the treatment of T2DM.

Fig. 1

Renal anatomy. Nephrons are predominantly located in the renal cortex, with the remainder at the cortico-medullary junction. Each nephron consists of a glomerulus, containing afferent and efferent capillaries, and a renal tubule, including proximal and distal sections and a collecting duct

Fig. 2

Glucose transporters in the renal proximal tubule. Data suggest approximately 90% of filtered glucose is reabsorbed in the first part (S1) of the proximal tubule and is mediated by SGLT2. The remaining 10% is reabsorbed in the distal (S2/S3) part of the tubule and this is mediated by SGLT1. This process is extremely efficient and virtually no glucose escapes into the urine of a healthy individual. Glucose is returned to the bloodstream via GLUT2 in the S1/S2 segment and via GLUT1 in the S3 segment of the proximal tubule

Fig. 3

Renal glucose handling before and after SGLT2 inhibition. SGLT2 inhibition reduces the transport maximum for glucose (TM_G), which decreases glucose reabsorption in the proximal renal tubule, and lowers the renal threshold so that urinary glucose excretion (i.e., glucosuria) occurs at a lower plasma glucose concentration (reproduced with permission from [48])

Fig. 4

SGLT2 inhibitors in late phase clinical development