Sodium Glucose Cotransporter 2 Inhibition in the Diabetic Kidney

An Update

Aleksandra Novikov; Volker Vallon

Disclosures

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

In This Article

Abstract and Introduction

Abstract

Purpose of review The sodium glucose cotransporter 2 (SGLT2) reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption, thereby lowering blood glucose levels, and have been approved as new antihyperglycemic drugs. Although the therapeutic strategy is very promising, many questions remain.

Recent findings Using validated antibodies, SGLT2 expression was localized to the brush border of the early proximal tubule in the human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional renal glucose reabsorption of 40–50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alfa cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers glomerular filtration rate in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy.

Summary The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors.

Introduction

Diabetes mellitus is a growing health concern worldwide.[1] Normalizing hyperglycemia is vital in slowing the progression of the disease process and preventing the devastating secondary consequences including cardiovascular disease and nephropathy. Inhibitors of sodium glucose cotransporter 2 (SGLT2) have recently been approved as new antihyperglycemic drugs in type 2 diabetes mellitus (T2DM). Studies are underway in type 1 diabetes mellitus (T1DM) using SGLT2 inhibitors as an add-on to insulin therapy. These compounds inhibit the reabsorption of glucose in the kidney, a process that is enhanced in diabetes, thereby spilling glucose into the urine and lowering blood glucose levels (Figs 1 and 2). In contrast to many of the current antidiabetic therapies, SGLT2 inhibitors can lower body weight, work independent of endogenous insulin, and have little risk of hypoglycemia (see[2–5] for review).

Figure 1.

Direct and indirect effects of SGLT2 inhibition on the kidney and other organs, and the potential for beneficial cardiovascular effects and nephroprotection as well as unwanted side-effects. PCKD, polycystic kidney disease. – and + indicate reduction and increase, respectively.

Figure 2.

The tubular hypothesis of diabetic glomerular hyperfiltration: effect of SGLT2 inhibition. (a) (1) Glucose reabsorption occurs via SGLT2 in the early PT and to a small degree via SGLT1 in the late PT; Na is reabsorbed via NHE3. (2) NaCl is reabsorbed via Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb. (3) Luminal NaCl concentration at the macula densa ([NaCl]) inversely regulates GFR via TGF. (4) Fluid delivery to the distal tubule (site of main tubular resistance) determines PBow which imposes inhibitory influence on GFR. (b) (1) Hyperglycemia and tubular growth increase Na/glucose reabsorption via SGLT2 and SGLT1 and increase Na reabsorption via NHE3. (2 and 3) This lowers [NaCl] at the macula densa and increases GFR via TGF. (4) The hyperreabsorption decreases fluid delivery to the distal tubule which reduces PBow and increases GFR. (c) (1 and 2) SGLT2 inhibitor blocks Na/glucose reabsorption via SGLT2 and potentially inhibits NHE3. (3 and 4) This increases [NaCl] at the macula densa and lowers GFR via TGF. (5) Inhibition of hyperreabsorption increases fluid delivery to the distal tubule which increases PBow and lowers GFR. (6) SGLT2 inhibition increases load to the outer medulla and Na reabsorption via SGLT1 and NKCC2. This may enhance medullary hypoxia unless counterbalanced by GFR reduction. GFR, glomerular filtration rate; PBow, hydrostatic pressure in Bowman space; PT, proximal tubule; SGLT2, sodium glucose cotransporter 2; TGF, tubuloglomerular feedback.

Although this new class of antidiabetic compounds is very promising, many questions remain. In this review, we will discuss new insights on the biology of SGLT2 and the consequences of SGLT2 inhibition on the kidney and beyond.

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