Optimizing SGLT inhibitor treatment for diabetes with chronic kidney diseases

Abstract

Diabetes induces glomerular hyperfiltration, affects kidney function, and may lead to chronic kidney diseases. A novel therapeutic treatment for diabetic patients targets the sodium–glucose cotransporter isoform 2 (SGLT2) in the kidney. SGLT2 inhibitors enhance urinary glucose, $\hbox {Na}^+$ and fluid excretion and lower hyperglycemia in diabetes by inhibiting $\hbox {Na}^+$ and glucose reabsorption along the proximal convoluted tubule. A goal of this study is to predict the effects of SGLT2 inhibitors in diabetic patients with and without chronic kidney diseases. To that end, we applied computational rat kidney models to assess how SGLT2 inhibition affects renal solute transport and metabolism when nephron population are normal or reduced (the latter simulates chronic kidney disease). The model predicts that SGLT2 inhibition induces glucosuria and natriuresis, with those effects enhanced in a remnant kidney. The model also predicts that the $\hbox {Na}^+$ transport load and thus oxygen consumption of the S3 segment are increased under SGLT2 inhibition, a consequence that may increase the risk of hypoxia for that segment. To protect the vulnerable S3 segment, we explore dual SGLT2/SGLT1 inhibition and seek to determine the optimal combination that would yield sufficient urinary glucose excretion while limiting the metabolic load on the S3 segment. The model predicts that the optimal combination of SGLT2/SGLT1 inhibition lowers the oxygen requirements of key tubular segments, but decreases urine flow and $\hbox {Na}^+$ excretion; the latter effect may limit the cardiovascular protection of the treatment.