Sodium–Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is now the principal cause of chronic kidney disease leading to end-stage kidney disease worldwide. As a primary contributor to the excess risk of all-cause and cardiovascular death in diabetes, DKD is a major contributor to the progressively expanding global burden of diabetes-associated morbidity and mortality. Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a newer class of antihyperglycemic agents that exert glucose-lowering effects via glycosuric actions. Preclinical studies and clinical trials of SGLT2 inhibitors have consistently demonstrated reduction of albuminuria and preservation of kidney function. In particular, SGLT2 inhibitors lower risk of congestive heart failure, a major cardiovascular complication in DKD. This Perspective summarizes proposed mechanisms of action for SGLT2 inhibitors, integrates these data with results of recent cardiovascular outcomes trials, and discusses clinical applications for patients with DKD. The American Diabetes Association/European Association for the Study of Diabetes Consensus Report published online in October 2018 recommends SGLT inhibitors as preferred add-on therapy for patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease, if kidney function is adequate. Results of the ongoing and just completed clinical trials conducted in patients with established DKD will facilitate further refinement of current guidelines.

Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

“…Pathological findings revealed that tubulointerstitial and vascular lesions tended to be more advanced in participants with type 2 diabetes and CKD with normoalbuminuria than those in participants with microalbuminuria or macroalbuminuria [11,14,15]. Because the possible mechanisms for the renoprotective effects of SGLT2 inhibitors are assumed to include not only reduction in glomerular hyperfiltration as a result of tubuloglomerular feedback restoration, but also improvement of tubulointerstitial damage [16,17], improved tubular cell injury may contribute to the greater beneficial effects of SGLT2 inhibitors in participants with type 2 diabetes and CKD with normoalbuminuria. Recent reports have shown a putative protective effect of SGLT2 inhibitors against tubular cell injury.…”

Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes

“…First, the avid glucose reabsorption in the proximal tubule of the subjects with diabetes is coupled with avid sodium reabsorption by sodium-glucose co-transporters (SGLTs), the so-called SGLTs. This results in decreased distal sodium delivery to the macula densa and increased renin release [18]. Second, a growing body of experimental evidence suggests that insulin itself can cause RAS activation in subjects with metabolic syndrome or diabetes that have insulin resistance and hyperinsulinemia.…”

Series: Implications of the recent CVOTs in type 2 diabetes

“…Finally, other trials in patients with CKD are ongoing, with the particularity of having included subjects with but also without T2DM [56,57]: this is the case for EMPA-KIDNEY [58] and DAPA-CKD [56,57]. Thus, these ongoing dedicated renal outcome trials will provide further guidance on the potential clinical role of SGLT2is in slowing the development and progression of renal impairment in individuals with T2DM.…”