Mechanistic evaluation of the effect of sodium-dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics

摘要

Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration-time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (T-max,T-glc) to reach maximum concentration of glucose (C-max,C-glc), and the delay of T-max,T-glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in C-max,C-glc was estimated to be 23%-28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.