Table 1.
Kidney-protective effects of sodium-glucose cotransporter 2 inhibitors
| Protective Effect | Mechanism | Comment |
|---|---|---|
| Hemodynamic benefits | Increased tubuloglomerular feedback; increased delivery of NaCl to macula densa causes adenosine-mediated vasoconstriction of the afferent arteriole and lowers intraglomerular pressure; efferent vasodilation may predominate in type 2 diabetes mellitus in the setting of renin-angiotensin blockade | A 3- to 6-ml/min reduction in GFR is common in first 2–3 wks of therapy caused by reduction in intraglomerular pressure; increased pressure in Bowman’s space may also contribute to the early eGFR decline |
| Improved glycemic control | Reduction in TM leads to glycosuria, the glucose-lowering effect diminishes as plasma glucose level declines and/or GFR falls due to diminished filtered load | In clinical trials, HgA1c decreases by 0.6%–1.0% versus placebo; the glycosuric effect is no longer evident as eGFR approaches 30–40 ml/min |
| Decreased glucose flux across cell | Decreased proximal tubular cell glucose entry limits abnormally high rates of glycolysis, potentially limiting kidney fibrosis | Increased glycolysis linked to the activation of HIF1α and the suppression of Sirt3 and increased epithelial-mesenchymal transition, activation of NLRP3 inflammasome |
| Natriuresis | Inhibition of SGLT2 is accompanied by reduced NHE3 activity, plasma volume is reduced | Contributes to the 4/2–mm Hg reduction in BP, tissue-bound Na+ is also reduced, despite reduced BP and plasma volume heart rate is not increased consistent with decreased sympathetic outflow |
| Perirenal fat | Decreased paracrine release of adipokines and proinflammatory cytokines | Decreased leptin release decreases central afferent input and lowers sympathetic outflow, albuminuria and glomerular injury are decreased |
| Weight loss | Urinary glucose loss corresponding to 200–400 kcal/d, increased energy expenditure associated with beiging of adipocytes | Visceral and subcutaneous fat mass is reduced likely to include perirenal fat, increases in fibroblast growth factor 21 contributes to reduction in fat mass |
| Improved metabolic flexibility | Loss of glucose in urine leads to a fasting-like state with a decreased insulin-glucagon ratio and increased ketogenesis | Decreased respiratory exchange ratio reflects increased fat oxidation, mTORC1 is suppressed and autophagy is restored in tubular cells and podocytes |
| Decreased tubular workload | Decrease Na+ entry into proximal tubular cell reduces ATP and O2 consumption | SGLT2is are associated with less risk of AKI |
| Increase hemoglobin concentration (3%) | Increased O2 consumption to reabsorb Na+ in downstream segments result in ↑ erythropoietin production | Hypoxia stimulates HIF2α, causing ↑ autophagy and ↓ inflammation |
| Increase plasma magnesium (Mg2+) | ↑ glucagon and PTH stimulate Mg2+ reabsorption in thick limb, upregulation of TRPM6/7 in DCT | SGLT2is may be useful in Mg2+ wasting disorders, decreased risk of arrhythmias and risk of diabetes mellitus |
| Decrease plasma uric acid | Increased tubular glucose competes with uric acid for reabsorption via GLUT9 | Reduction in risk of gout flares, decreased risk of CKD due to hyperuricemia |
| Decrease risk of hyperkalemia from RAASi | Increased flow and Na+ delivery augment K+ secretion in the distal nephron | SGLT2is alone have minimal effects on plasma K+ concentration |
TM, tubular maximum; HgA1c, glycated hemoglobin; HIF1α, hypoxia-inducible factor 1α; Sirt3, sirtuin 3; NLRP3, NOD-, LRR-, and pyrin domain–containing protein 3; SGLT2, sodium-glucose cotransporter 2; NHE3, Na+-H+ antiporter 3; mTORC1, mammalian target of rapamycin complex 1; SGLT2i, sodium-glucose cotransporter 2 inhibitor; HIF2α, hypoxia-inducible factor 2α; PTH, parathyroid hormone; TRPM6/7, transient receptor potential melastatin 6/7; DCT, distal convoluted tubule; GLUT9, glucose transporter 9; RAASi, renin-angiotensin-aldosterone system inhibitor.