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

What is the Consequence of Increasing Glucose Delivery to the Segments Downstream of the Early Proximal Tubule by Sodium Glucose Cotransporter 2 Inhibition?

The main side-effect of SGLT2 inhibition is an increased risk of genital infections and, to a relatively lesser extent, urinary tract infections (Fig. 1). There is some remaining discussion on the precise role of glucosuria as a causative factor for these infections.[45] Importantly, upper urinary tract infection (pyelonephritis) is not increased by SGLT2 inhibitors. Humans with familial renal glycosuria because of mutations in SGLT2 do not show signs of general renal tubular dysfunction or other pathological changes; in accordance, genetic or pharmacologic inhibition of SGLT2 in nondiabetic rodents induced glucosuria with no changes in kidney injury markers, or only minor increases in markers of tubular growth and protective mechanisms, respectively.[4,5]

Using mathematical modeling of the rat proximal tubule, it was proposed that SGLT2 inhibition reduced proximal tubular Na reabsorption, but increased oxygen consumption in the outer medullary S3 segment by increasing Na and glucose delivery to this segment, and inhibiting passive paracellular reabsorption, and thereby increasing active transcellular reabsorption.[46] The model further predicted that diabetes increased proximal tubular oxygen consumption mostly as a consequence of glomerular hyperfiltration and increased tubular work load. Therefore, the net effect of SGLT2 inhibition on proximal tubular Na reabsorption and oxygen consumption was proposed to largely depend on the extent of the GFR-lowering effect.[46] Along these lines, acute nonselective SGLT inhibition improved cortical oxygen tension in streptozotocin-induced T1DM rats, whereas it reduced medullary oxygen tension in control and diabetic rats.[47] These modeling and experimental data indicate that SGLT2 inhibition may enhance medullary hypoxia by inhibiting paracellular reabsorption in the S3 segment and redistribution of Na reabsorption to the S3 segment and medullary thick ascending limb, whereas such an effect is counteracted by the reduction in blood glucose and GFR (Figs 1 and 2). Longer-term experimental studies and studies in humans are needed, as well as studies that address the question of whether conditions that increase renal medullary hypoxia (e.g., ischemia-reperfusion or nephrotoxins) increase the sensitivity to SGLT2 inhibition. In this regard, the EMPA-REG OUTCOME trial found that the proportions of patients with adverse events, including acute renal failure, were similar in patients treated with SGLT2 inhibitor versus placebo. In a subgroup analysis of patients with GFR < 60 ml/min (CKD3), there was a favorable, although not statistically significant, trend toward the primary cardiovascular outcome in the empagliflozin treatment group.[32]

Studies using a rat model of polycystic kidney disease (PCKD) found that SGLT2 inhibition for 6 weeks increased cyst volume and induced a 23% higher total kidney weight, without reducing creatinine clearance or changing renal cyclic adenosine monophosphate content or increasing staining for Ki67 as a marker of cell proliferation.[48] This could be of relevance if prescribing SGLT2 inhibitors to PCKD patients. Further dedicated experimental and clinical studies, and careful evaluation of ongoing longer-term clinical studies, will help to refine our understanding of the renal pharmacodynamics and safety of SGLT2 inhibitors (Fig. 1).

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