title: SGLT2 Inhibitors and the Diabetic Kidney.
abstract: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects.
authors.affiliation: Department of Medicine, University of Padua, Padua, Italy paola.fioretto@unipd.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Fioretto
authors.affiliation: Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambon
authors.affiliation: Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rossato
authors.affiliation: Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Busetto
authors.affiliation: Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Vettor
mesh_terms: D000419:Albuminuria / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000517:prevention & control*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000187:drug effects; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin