Blockade of the RAAS in diabetes mellitus is the cornerstone of primary and secondary renal protection in T2D and of secondary prevention in T1D [12–14]. From a mechanistic perspective, angiotensin converting enzyme (ACE) inhibition with enalapril for 3 weeks significantly attenuates hyperfiltration as measured by inulin clearance in adolescent patients with T1D . Interestingly and in agreement with the observations by others , ACE inhibition failed to fully attenuate hyperfiltration in this study [glomerular filtration rate (GFR) decline from 178 to 143 ml/min/1.73 m2 or 19.7% decline in GFR]. Subsequent human mechanistic work has shown that dual RAAS blockade with ACE inhibition and a direct renin inhibitor did not result in more substantial hemodynamic effects in T1D patients . When translated from physiological experiments to clinical trials, use of RAAS blockade monotherapies has also failed to fully prevent the renal injury . Moreover, similar to the human mechanistic work, combination RAAS blockade strategies in large randomized controlled trials (RCTs) examining the renal and cardiovascular outcomes have shown that not only is this approach ineffective, but also the risks of dual RAAS blockade clearly outweigh the benefits [19▪▪,20,21]. For example, the Veterans Affairs Nephropathy in Diabetes study in patients with overt diabetic nephropathy was stopped early because of the concerns about the increased risks of hyperkalemia and acute kidney injury without cardiac or renoprotective benefits [19▪▪]. In summary, therapies targeting neurohormonal pathways have thus far only partially corrected the early hemodynamic abnormalities in T1D, lead to incomplete clinical protective effects and can cause serious adverse effects. The development of alternative, well tolerated renal-protective therapies in diabetes mellitus is therefore critical.
Previous experimental models of diabetes have noted increased glucose reabsorption at the proximal tubule, because of increased gene expression of SGLT2 [22,23]. Similar increases in SGLT2 expression levels have also been documented in humans . The first pharmacological sodium–glucose transport inhibitor, phlorizin, competitively inhibits both SGLT1 and SGLT2 in the proximal tubule, with a 10-fold higher affinity for SGLT2 . Phlorizin was recognized to cause glucosuria in animals and was used as a basic model of osmotic diuresis, because of induction of polyuria, polyphagia, thirst and weight loss . Subsequent use of phlorizin in humans was limited to a single historical study, because of poor oral availability and gastrointestinal side-effects due to dual SGLT 1/2 inhibition [27,28▪]. Phlorizin was, however, used as a physiological tool in animal models and demonstrated promising effects on glycemic control and on renal function, as discussed below . To take advantage of the glycemic and metabolic effects of increased glycosuria, without adverse effects from gastrointestinal malabsorption of glucose, selective SGLT2 inhibitors have been developed, including empagliflozin , dapagliflozin , canagliflozin  and others .
Beyond the salutary effects on metabolic parameters and BP in patients with T1D and T2D, the influence of SGLT2 inhibition as a potential renal-protective therapy against diabetic nephropathy has been the source of considerable interest, because of the effects on renal tubular function, including effects on hyperfiltration.
Alterations in tubuloglomerular feedback have been associated with early renal hemodynamic functional abnormalities in the experimental models of diabetes mellitus, including renal hyperfiltration, for more than 30 years . Subsequent work implicated the role of tubular factors in the pathogenesis of hyperfiltration in patients with diabetes mellitus . Elegant preclinical studies by Blantz, Thomson, Vallon and others have demonstrated the basis for the tubular hypothesis, as reviewed elsewhere . In brief, hyperglycemia leads to an increased filtered glucose load at the proximal tubule and an increased SGLT2 mRNA expression [22,23]. As a consequence, more glucose is reabsorbed with sodium via SGLT2, leading to reduced distal sodium delivery to the macula densa and less sodium transport into macula densa cells. As this sodium transport is energy dependent, decreased sodium transport requires less ATP breakdown, resulting in a decline in adenosine production, which is the byproduct of ATP utilization. As adenosine is a potent vasoconstrictor, reduced adenosine activity causes afferent arteriolar vasodilatation, leading to hyperfiltration. Under normal, nondiabetic physiological conditions, reduced sodium delivery to the macula densa occurs as a result of intravascular volume depletion, and should elicit an afferent arteriolar vasodilatory response to maintain renal perfusion and avoid acute kidney injury. However, increased proximal sodium reabsorption with increased SGLT2 activity triggers the same teleological response via low production of adenosine, leading to inappropriate afferent renal arteriolar vasodilatation, increased glomerular capillary hydrostatic pressure and hyperfiltration . The importance of adenosine-mediated vasoconstriction has been demonstrated in the experimental models of T1D, as genetic knockout of the adenosine A1 receptor exaggerates renal hyperfiltration, leading to pronounced albuminuria and histological evidence of nephropathy [40,41].
In the experimental models of T2D, sodium–glucose cotransport inhibition is associated with a similar renal protective profile. For example, phlorizin administration prevents hyperfiltration, renal hypertrophy and proteinuria in a model of T2D, and selective SGLT2 inhibition with T-1095 exerts similar effects on proteinuria, in addition to decreased mesangial matrix expansion . Finally, in the BTBR ob/ob model of T2D, empagliflozin was recently reported to attenuate renal hypertrophy, albuminuria and markers of renal inflammation [49▪].
To date, because of the availability of appropriate pharmacological probes, most clinical studies examining the physiological basis for hyperfiltration have focused on the neurohormonal hypothesis. Previous work has therefore used RAAS blockers and protein kinase C inhibitors to promote efferent vasodilatation, as well as nitric oxide synthase and cyclooxygenase-2 inhibitors to promote afferent constriction [15,50–52]. Unfortunately, blockade of these pathways has revealed only partial attenuation of hyperfiltration, suggesting a possible role for alternative mechanisms in humans, including tubular factors.
On the basis of the compelling experimental data implicating increased SGLT2 activity in the pathogenesis of hyperfiltration and diabetic nephropathy, we examined the effect of empagliflozin on renal hyperfiltration in patients with uncomplicated T1D in an 8-week open-label, stratified clinical trial [53▪▪]. The safety and efficacy of empagliflozin as an add-on to insulin was examined to determine the impact on hyperfiltration and metabolic parameters. Inclusion criteria were men and women greater than 18 years of age with T1D, HbA1C levels of 6.5–11.0%, normal BP not on RAAS inhibitors and preserved estimated GFR (eGFR) of at least 60 ml/min/1.73 m2. Similar to responses in streptozotocin-induced diabetes mellitus animals, treatment with empagliflozin 25 mg daily decreased GFR as measured by inulin clearance under clamped euglycemic conditions from 172 ± 23 to 139 ± 25 ml/min/1.73 m2 in patients with baseline hyperfiltration [53▪▪]. This 19.2% decline in GFR occurred in conjunction with significantly decreased renal blood flow and an increase in renal vascular resistance, and exaggerated glucosuric responses, likely reflecting an increase in the afferent arteriolar tone because of increase in distal tubular solute delivery . Similar responses were observed in hyperfiltering patients under clamped hyperglycemic conditions. Interestingly, after empagliflozin treatment for 8 weeks, GFR, renal blood flow and renal vascular resistance remained unchanged in patients with normal baseline GFR. Acute effects of SGLT2 inhibition on GFR are unlikely to be related to RAAS blockade, as both empagliflozin and dapagliflozin increase, rather than suppress, plasma markers such as aldosterone and angiotensin II [53▪▪,55▪▪], as well as urinary ACE2, ACE and angiotensinogen, possibly on the basis of plasma volume contraction expected with these agents .
Dedicated renal protection studies have not yet been completed in humans, although such studies are currently underway [Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial – NCT02065791]. Nevertheless, existing clinical trial data in T2D patients have reported that SGLT2 inhibition is associated with effects on eGFR and proteinuria. In patients with T2D and stages 1–4 chronic kidney disease (CKD), SGLT2 inhibition is associated with an acute decline in eGFR of between 3 and 8 ml/min/1.73 m2 over 3–4 weeks, which is reversible after drug discontinuation [57,58,59▪▪]. Over this same time interval, empagliflozin reduces albuminuria in T2D patients with CKD , and similar observations have been made with other SGLT2 inhibitors [59▪▪]. Of specific interest for patients with CKD stage 3, dapagliflozin treatment for 24 weeks reduced albuminuria, BP and weight compared with placebo, even though HbA1c did not change . Dapagliflozin also reduced eGFR acutely in conjunction with albuminuria, followed by the maintenance of stable renal function over 104 weeks of subsequent treatment . Therefore, similar to the animal models of diabetic nephropathy [44▪▪], effects on BP, eGFR, weight and albumin excretion may be achieved independent of HbA1c lowering in patients with T2D and CKD (Fig. 2). Finally, in addition to the indirect effects of SGLT2 inhibition on renal protection via BP lowering, this class of agents is associated with other ‘off-target’ clinical effects that may further contribute to renal protection. These other indirect mechanisms include reductions in baseline insulin dosing of up to 20%, which may stabilize or decrease weight and BP parameters [53▪▪], and uric-acid-lowering effects, as discussed by others . As uric acid lowering may be renal protective , the consistent decline in uric acid reported with SGLT2 inhibitors may be clinically significant.
Why is the salt paradox of potential clinical importance? T1D is characterized by renal sodium retention and increased total body sodium, which may increase the risk of hypertension . It is therefore the standard clinical care to recommend that patients restrict salt intake, especially in the context of proteinuria, hypertension, CKD or the use of RAAS inhibitors. However, if sodium restriction promotes an increase in intraglomerular pressure and hyperfiltration, this may promote a BP-independent deleterious effect in the kidney. Similarly, it has been noted that salt restriction in T1D patients may be associated with increased all-cause mortality and ESRD . In light of the potential for SGLT2 inhibitors to modify the proximal tubular responses to salt intake, further work is required to determine the role of this novel class on the salt paradox and renal autoregulation in diabetes mellitus.
On the basis of the existing preclinical and clinical data using surrogate renal endpoints, the rationale for SGLT2 inhibition as a renal-protective therapy is compelling. However, it is important to recognize that clinical studies using other strategies such as dual RAAS blockade and endothelin antagonism generated promising initial results based on the endpoints such as proteinuria and changes in eGFR, but ultimately failed to translate into useful renal-protective approaches . Outcomes of ongoing, adequately powered trials are therefore eagerly awaited to assess the clinical utility of SGLT2 inhibition as a renal-protective therapy. In addition, as RAAS inhibition therapies are ineffective for renal protection in normotensive, normoalbuminuric T1D patients, the potential for primary renal protection with SGLT2 inhibition merits investigation in the long-term studies . Finally, in light of the recent preclinical data demonstrating additive renal-protective effects with the SGLT2 inhibition and RAAS inhibition, human mechanistic studies are needed to examine the safety and physiological effects of this combination, as this approach targets both neurohormonal and tubular factors associated with the initiation and progression of diabetic nephropathy.
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