SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1

Abstract

Inhibitors of the Na+-glucose cotransporter SGLT2 enhance urinary glucose and urate excretion and lower plasma urate levels. The mechanisms remain unclear, but a role for enhanced glucose in the tubular fluid, which may interact with tubular urate transporters, such as the glucose transporter GLUT9 or the urate transporter URAT1, has been proposed. Studies were performed in nondiabetic mice treated with the SGLT2 inhibitor canagliflozin and in gene-targeted mice lacking the urate transporter Glut9 in the tubule or in mice with whole body knockout of Sglt2, Sglt1, or Urat1. Renal urate handling was assessed by analysis of urate in spontaneous plasma and urine samples and normalization to creatinine concentrations or by renal clearance studies with assessment of glomerular filtration rate by FITC-sinistrin. The experiments confirmed the contribution of URAT1 and GLUT9 to renal urate reabsorption, showing a greater contribution of the latter and additive effects. Genetic and pharmacological inhibition of SGLT2 enhanced fractional renal urate excretion (FE-urate), indicating that a direct effect of the SGLT2 inhibitor on urate transporters is not absolutely necessary. Consistent with a proposed role of increased luminal glucose delivery, the absence of Sglt1, which by itself had no effect on FE-urate, enhanced the glycosuric and uricosuric effects of the SGLT2 inhibitor. The SGLT2 inhibitor enhanced renal mRNA expression of Glut9 in wild-type mice, but tubular GLUT9 seemed dispensable for the increase in FE-urate in response to canagliflozin. First evidence is presented that URAT1 is required for the acute uricosuric effect of the SGLT2 inhibitor in mice.

SGLT2 inhibition to address the unmet needs in diabetic nephropathy

“…In addition, as insulin induces URAT1 expression, SGLT2i may also enhance uricosuria by ameliorating glucose control and thus suppressing insulin. 25 Treatment with SGLT2i also lowers BP without a compensatory increase in heart rate. 26 In a meta-analysis of 22 528 patients from 43 randomized controlled trials (RCTs), mean difference in systolic and diastolic BP between SGLT2i and placebo/comparators were −2.46 and −1.46 mm Hg, respectively.…”

“…GLUT9 exchanges glucose for UA and has been implicated in the uricosuric effect of SGLT2 inhibition . However, recent evidence in experimental animals indicates that GLUT9 is dispensable, while URAT1 is required for the uricosuric response to SGLT2i . Inhibition of URAT1‐mediated UA tubular reabsorption by glycosuria is considered the predominant mechanism.…”

“…Inhibition of URAT1‐mediated UA tubular reabsorption by glycosuria is considered the predominant mechanism. In addition, as insulin induces URAT1 expression, SGLT2i may also enhance uricosuria by ameliorating glucose control and thus suppressing insulin …”

“…23,24 However, recent evidence in experimental animals indicates that GLUT9 is dispensable, while URAT1 is required for the uricosuric response to SGLT2i. 25 Inhibition of URAT1-mediated UA tubular reabsorption by glycosuria is considered the predominant mechanism. In addition, as insulin induces URAT1 expression, SGLT2i may also enhance uricosuria by ameliorating glucose control and thus suppressing insulin.…”

Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events

“…Even though the several RCTs have provided a well-defined safety profile, few other rare and debated potential side effects have been reported [75]: euglycaemic ketoacidosis, especially in T1DM or during acute illness, bone fractures, Fournier's gangrene, lower limb amputations, the latter three without agreement between RCTs and not confirmed in real-world evidence [76]. Heart protection -Improved oxygen delivery (stimulation of renal erythropoietin secretion) [70] -Reduced sympathetic nervous system activity [31] -Improved mitochondrial respiration and coronary vasodilation (inhibition of sodium/hydrogen exchanger 1) [97] -Reduced inflammation and oxidative stress (improved mitochondrial function) [98] leading to reduced fibrosis -Improved contractility (inhibition of calcium/calmodulin-dependent kinase II activity) [99] -Improved myocardial efficiency (utilization of fatty substrates) [100] -Epigenetic modifications [101] -Improved metabolism and slowed kidney disease progression [102] Vascular protection -Reduced low-grade tissue inflammation [103] -Reduced oxidative stress and improved endothelial function [104] -Reduced epicardial fat deposition and modulation of leptin and renin-angiotensin-aldosterone system [105] -Reduced vascular stiffness [49] -Increased vascular progenitor cells [106] -Improved metabolism and cardiorenal health [102] Renal protection -Reduced tubular senescence and glomerular loss [107] -Reduced renal inflammation, oxidative stress and fibrosis [108,109] -Reduced energy demand (ATP production) [70] -Reduced uric acid levels [110] -Improved metabolism and cardiovascular health [102] Metabolic protection -Reduced glycated hemoglobin levels [111] -Reduced body weight and adiposity [112] -Reduced uric acid levels [110] -Reduced liver fat [113] ATP: adenosine triphosphate.…”