Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans?

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30-50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible.

FIG. 1.

SGLT2 inhibitors in late-stage clinical trials.

FIG. 2.

Plasma dapagliflozin concentration as a function of time following an oral dose of 20 mg in healthy volunteers. Conc., concentration. Modified from Fig. 4 of Komoroski et al. (23).

FIG. 3.

Schematic PK/PD graphs of empagliflozin (BI 10773). UGE rate–time profiles are shown in dotted line (10 mg-PD), dashed line (100 mg-PD), and dashed-dotted line (400 mg-PD). Plasma concentration–time profiles are shown in solid lines. Three representative doses are shown: 10, 100, and 400 mg. Conc., concentration. Modified from Port et al. (22) and Dugi and Mark (26).