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.

Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial

“…Although we cannot confirm through this single-arm study that SGLT2 inhibition as adjunctive-to-insulin therapy poses a low risk of hypoglycemia, we speculate that it may be advantageous because of the insulin-independent mechanism of action, the partial inhibition of glucose reabsorption by SGLT2 inhibitors (11), the diminished effect of SGLT2 owing to a physiological decline in glomerular filtration rate during sympathetic nervous system activation associated with hypoglycemia (12), and the putative compensatory increase in hepatic gluconeogenesis (13). Finally, SGLT2 inhibition in insulin-treated patients with type 2 diabetes does not substantially increase the risk of hypoglycemia (8,9).…”

Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes

“…Of note, over the full 52-week treatment period, including the treatto-target period, the proportion of patients with confirmed hypoglycemic AEs was similar in all treatment groups. This might be explained by differences in insulin titration in the empagliflozin and placebo arms due to the insulinindependent mechanism of action of empagliflozin (13); the incomplete inhibition of renal glucose reabsorption by empagliflozin (19); a diminished effect of SGLT2 inhibition at low glucose levels due to physiological decline in glomerular filtration rate (due to sympathetic nervous system activation) (20); a compensatory increase in hepatic gluconeogenesis (21); or a combination of these factors.…”

Diabetic ketoacidosis without hyperglycemia as a complication of SGLT2 inhibitors treatment

“…An increased level of SGLT2 mRNA was found in the cells isolated from proximal tubules of patients with type 2 diabetes compared to healthy people [19]. However, SGLT2 inhibitors only block reabsorption of approximately 30-50% of glucose excreted into primary urine [20].…”