SGLT2 Inhibition for Diabetic and Non-diabetic Kidney Disease

Abstract

Chronic kidney disease (CKD) can be progressive, and its prognosis is worse because of increased mortality when it is associated with diabetes and cardiac disease. The outcomes of diabetic kidney disease (DKD) need to be improved, despite multifactorial interventions including glucose and blood pressure (BP) control, and the use of renin-angiotensin system (RAS) inhibitors, statins, and aspirin. Recent clinical trials suggest that sodium-glucose cotransporter-2 (SGLT2) inhibitors offer additional cardiorenal protection in DKD and non-diabetic CKD on top of RAS inhibition. The action of SGLT2 inhibitors is derived from the proximal tubule of the kidney, but their systemic effects beyond glucose-lowering involve hemodynamic and non-hemodynamic mechanisms. First, SGLT2 inhibitors restore tubuloglomerular feedback and relieve glomerular hypertension and albuminuria. Second, natriuresis and renal glycosuria lead to fluid and weight loss, resulting in BP lowering and prevention of heart failure. Third, SGLT2 inhibitors have anti-inflammatory and anti-oxidative actions that can reduce renal and cardiac inflammation and fibrosis, probably via adenosine monophosphate-activated protein kinase and sirtuin-1 activation. Finally, the proximal tubular workload is relieved, accompanied by increased erythropoiesis. Hypoxia-inducible factor 1 may be stimulated by renal outer medullary hypoxia when tubular sodium transport shifts from the proximal convoluted tubule to the proximal straight tubule and thick ascending limb, due to SGLT2 inhibition. These effects may also be beneficial in non-diabetic CKD, and we anticipate that SGLT2 inhibitors will prove effective for albuminuria reduction and preservation of kidney function in primary kidney diseases, including glomerulonephritis.