Sodium Glucose Cotransporter 2 Inhibition in the Diabetic Kidney

An Update

Aleksandra Novikov; Volker Vallon


Curr Opin Nephrol Hypertens. 2016;25(1):50-58. 

In This Article

Does Sodium Glucose Cotransporter 2 Inhibition Provide Kidney Protection Beyond Lowering Blood Glucose Levels?

Diabetes is a leading cause of CKD and end stage renal disease. SGLT2 inhibition may induce beneficial effects on the reno–cardiovascular system by lowering blood glucose, body weight, and blood pressure (see above). The pathophysiology of diabetic kidney disease is still poorly understood. T1DM and T2DM can lead to early kidney growth, glomerular hyperfiltration, and proinflammatory processes which have been associated with a greater risk for later nephropathy.[12] Beneficial effects on these parameters may have nephroprotective potential, and SGLT2 inhibition could affect these parameters through lowering blood glucose levels or because the kidneys sense hyperglycemia and glucotoxicity in part through SGLT2-mediated glucose uptake. To address this issue requires considering the metabolism, needs, and complexity of the in-vivo renal system.

Sodium Glucose Cotransporter 2 Inhibition Lowers Hyperfiltration Independent of Lowering Blood Glucose

Hyperglycemia increases the glucose delivery to the proximal tubule and is associated with tubular growth. According to the tubular hypothesis of glomerular hyperfiltration in the diabetic kidney (for review see[12]), these changes increase proximal tubular reabsorption of glucose and Na via SGLT2 and SGLT1, of Na via Na/H exchanger NHE3, and secondarily of Cl, K and fluid; this in turn reduces the tubular Na, Cl, K, and fluid load to the macula densa and distal tubule; to restore the NaCl and fluid load to the early distal tubule, the GFR is increased through the physiology of tubuloglomerular feedback as well as the reduction in Bowman space hydrostatic pressure, which is a determinant of the filtration pressure and is sensitive to distal tubular fluid load (Fig. 2). The quantitative role of glucose reabsorption in diabetic glomerular hyperfiltration and mechanistic insights have been demonstrated in rats by local application into the early proximal tubule of a nonselective SGLT inhibitor[40] and by systemic application of a selective SGLT2 inhibitor,[41] as well as by studies in diabetic SGLT2 knockout mice.[13] All these maneuvers lowered GFR, and the GFR effect did not require a lowering of blood glucose levels, but was associated with an increased NaCl concentration at the macula densa[40,41] and an increase in the hydrostatic pressure in Bowman space[40] (Figs 1 and 2). In accordance, SGLT2 inhibition for 15 weeks prevented glomerular hyperfiltration in T1DM Akita mice.[14] Recent studies confirmed such an effect in humans. In an 8-week study of T1DM patients, SGLT2 inhibition decreased GFR by 19% in patients with baseline hyperfiltration; again, this effect was independent of blood glucose lowering.[42] SGLT2 inhibition for 3 weeks also induced a small reduction in estimated GFR and in albumin to creatinine ratios in T2DM patients with a baseline GFR of 30–50 ml/min; these effects were mostly maintained over 26 weeks.[43] Similar effects were observed for up to 52 weeks of therapy in T2DM patients with CKD stage 2–3.[24] Assuming that CKD is associated with deleterious glomerular hyperfiltration in the remaining intact nephrons, and therefore a high glucose delivery to the individual early proximal tubule, the reduction in GFR in response to SGLT2 inhibition is expected under these conditions in accordance with the tubular hypothesis[4] (Fig. 2).

Sodium Glucose Cotransporter 2 Inhibition may Lower Early Kidney Growth and Inflammation by Lowering Blood Glucose

SGLT2 gene knockout decreased blood glucose levels from 470 to 300 mg/dl in streptozotocin-induced T1DM mice, but did not attenuate the increase in kidney weight, markers of kidney growth, and inflammation or injury observed over a period of 4.5 months.[13] SGLT2 inhibition in T1DM Akita mice lowered blood glucose from 500 to 200 mg/dl; at such a strong blood glucose effect (see paper for explanations), SGLT2 inhibition attenuated kidney growth, glomerular growth, molecular markers of renal growth, albuminuria, and inflammation, apparently in proportion to blood glucose levels.[14] SGLT2 inhibition also reduced blood glucose from 400 to 200 mg/dl in T2DM ob/ob mice; again this was associated with a decrease in renal hypertrophy, albuminuria, and markers of inflammation and mesangial matrix expansion.[15] Furthermore, in T1DM endothelial nitric oxide synthase knockout mice with matched high blood glucose levels across all groups, those with SGLT2 inhibition showed no benefit on glomerulosclerosis, tubular atrophy, or tubulointerstitial fibrosis, whereas those treated with an angiotensin II AT1 receptor antagonist did.[44] Together, these studies are consistent with the notion that SGLT2 inhibition can lower early growth and inflammation in the diabetic kidney primarily by lowering blood glucose (Fig. 1).