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Sodium–glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy

Škrtić, Marko; Cherney, David Z.I.

Current Opinion in Nephrology and Hypertension: January 2015 - Volume 24 - Issue 1 - p 96–103
doi: 10.1097/MNH.0000000000000084
HORMONES, AUTACOIDS, NEUROTRANSMITTERS AND GROWTH FACTORS: Edited by Mark Cooper and Merlin Thomas
Editor's Choice

Purpose of review Renal hyperfiltration has been used as a surrogate marker for increased intraglomerular pressure in patients with diabetes mellitus. Previous human investigation examining the pathogenesis of hyperfiltration has focused on the role of neurohormones such as the renin–angiotensin–aldosterone system (RAAS). Unfortunately, RAAS blockade does not completely attenuate hyperfiltration or diabetic kidney injury. More recent work has therefore investigated the contribution of renal tubular factors, including the sodium–glucose cotransporter, to the hyperfiltration state, which is the topic of this review.

Recent findings Novel sodium–glucose cotransporter-2 (SGLT2) inhibitors reduce proximal tubular sodium reabsorption, thereby increasing distal sodium delivery to the macula densa, causing tubuloglomerular feedback, afferent vasoconstriction and decreased hyperfiltration in animals. In humans, SGLT2 inhibition was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients with type 1 diabetes. In clinical trials of type 2 diabetes, SGLT2 is associated with significant renal effects, including modest, acute declines in estimated glomerular filtration rate followed by the maintenance of stable renal function, and reduced albuminuria.

Summary Existing data are supportive of a potential renal-protective role for SGLT2 inhibition in patients with diabetes. Dedicated renal outcome trials are ongoing and have the potential to change the clinical practice.

Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Correspondence to David Z.I. Cherney, MD, PhD, FRCP(C), Toronto General Hospital, 585 University Avenue, 8N-845, Toronto, ON, Canada M5G 2N2. Tel: +1 416 340 4151; fax: +1 416 340 4999; e-mail: david.cherney@uhn.on.ca

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INTRODUCTION

Diabetes mellitus is a growing public health concern worldwide. The prevalence of diabetes mellitus is increasing and is estimated to be at 5.8–12.9% in the United States [1]. Of the known complications associated with diabetes mellitus, diabetic nephropathy is of particular concern and has become the most common cause of end-stage renal disease (ESRD) in the developed countries [2]. Recent research efforts have therefore focused on the prevention of progressive kidney function decline toward ESRD in type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) patients. Accordingly, it is important to understand the pathogenic mechanisms that promote the initiation and progression of early diabetic nephropathy.

In terms of early functional changes implicated in the early pathogenesis of diabetic nephropathy, renal hyperfiltration has been identified as a surrogate marker of increased intraglomerular pressure [3], leading to albuminuria and renal function decline [3–5]. Hyperfiltration is present in approximately 50% of patients with T1D and T2D [6], and is also commonly observed in prediabetic states, including impaired fasting glucose, in the general population [7]. Although the pathophysiology of renal hyperfiltration is incompletely understood, both glomerular hemodynamic abnormalities due to neurohormonal activation and tubular factors have been most closely linked with this condition. The hemodynamic or neurohormonal hypothesis of hyperfiltration has focused on the changes in afferent and efferent arteriolar resistances within the glomerulus, primarily because of renin–angiotensin–aldosterone system (RAAS) activation, resulting in increased hydrostatic pressure, with consequent hyperfiltration [6]. The consequent decline in intraglomerular pressure with RAAS blockade has provided the basis for most renal-protective therapies in patients with diabetic nephropathy over the last 20 years. Unfortunately, the clinical protective effects of RAAS blockade are limited, highlighting the need for non-RAAS-based therapies [8]. In contrast to the neurohormonal hypothesis, the tubular hypothesis has implicated the characteristic increase in sodium reabsorption at the proximal tubule via sodium–glucose cotransporter-2 (SGLT2) as the major cause of hyperfiltration through effects on tubuloglomerular feedback and afferent vasodilatation [9] (Fig. 1). As a result of the recent availability of SGLT2 inhibitors as therapeutic agents, animal and humans studies have highlighted the importance of the tubular hypothesis related to hyperfiltration, as well as the potential role of this emerging class as a renal protective therapy [10,11]. The role of SGLT2 inhibition in the prevention of progressive diabetic nephropathy will therefore be discussed in detail in this review.

FIGURE 1

FIGURE 1

Box 1

Box 1

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CURRENT TREATMENT STRATEGIES TARGETING THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM: EFFECTS ON HYPERFILTRATION AND ON DIABETIC NEPHROPATHY

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 [15]. Interestingly and in agreement with the observations by others [16], 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 [17]. When translated from physiological experiments to clinical trials, use of RAAS blockade monotherapies has also failed to fully prevent the renal injury [18]. 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.

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THE RATIONALE FOR SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITION IN DIABETES MELLITUS

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 [24]. 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 [25]. 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 [26]. 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 [11]. 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 [29], dapagliflozin [30], canagliflozin [31] and others [32].

Selective SGLT2 inhibition is associated with significant improvements in glycated hemoglobin (HbA1c), body weight and blood pressure (BP) in patients with T2D, as reviewed elsewhere [33]. We have also recently demonstrated that treatment with empagliflozin for 8 weeks has similar effects in young patients with T1D [34▪▪,35▪▪]. In this 8-week, proof-of-concept trial, empagliflozin reduced body weight and waist circumference significantly, HbA1c by 0.4%, daily insulin doses by 20% and the rate of symptomatic hypoglycemic events. SBP, which was, by design, within the normal range at baseline, also decreased significantly by a modest amount (approximately 3 mmHg), which we attributed to the effects on intravascular volume and reduced arterial stiffness [36].

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.

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SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITION AND DIABETIC NEPHROPATHY IN THE EXPERIMENTAL MODELS OF DIABETES MELLITUS

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 [37]. Subsequent work implicated the role of tubular factors in the pathogenesis of hyperfiltration in patients with diabetes mellitus [38]. Elegant preclinical studies by Blantz, Thomson, Vallon and others have demonstrated the basis for the tubular hypothesis, as reviewed elsewhere [39]. 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 [39]. 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].

On the basis of the first principles, SGLT2 inhibition would be expected to increase distal sodium delivery, thereby increasing adenosine production, causing afferent vasoconstriction, a fall in renal blood flow, decreased hyperfiltration and reduced renal injury. Genetic SGTL2 knockout studies have therefore been used to elucidate the role of tubular factors in the pathogenesis of early diabetic nephropathy in streptozotocin-induced models of T1D and demonstrated attenuated hyperfiltration responses [42▪▪]. To determine whether pharmacological SGLT2 inhibition reduces hyperfiltration, micropuncture studies have examined single-nephron GFR (SNGFR) and renal tubular solute delivery to the macula densa before and after SGLT2 inhibition. When hyperglycemic, streptozotocin-induced diabetic rats were treated with the SGLT2 inhibitor dapagliflozin, proximal sodium reabsorption decreased by 70%, in conjunction with an acute reduction in SNGFR [43]. In the Akita mouse model of T1D, empagliflozin is associated with similar effects on hyperfiltration, and also attenuated increases in kidney weight, glomerular size and renal mRNA expression of inflammatory markers such as nuclear factor kappa-beta, CCL2, CD14, IL6 and TIMP-2 [44▪▪]. In this study, effects on hyperfiltration were independent of glucose-lowering effects. Similar effects of sodium–glucose cotransport inhibition on nuclear factor kappa-beta and IL6 have been reported in vitro [45]. SGLT2 inhibition with ipragliflozin similarly attenuates hyperfiltration and reduces albuminuria [46▪]. Furthermore, ipragliflozin reduces oxidative stress levels, as well as the plasma markers of inflammation such as C-reactive protein and IL-6. In-vitro studies using phlorizin have reported similar suppressive effects on measures of oxidative stress [47].

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 [48]. Finally, in the BTBR ob/ob model of T2D, empagliflozin was recently reported to attenuate renal hypertrophy, albuminuria and markers of renal inflammation [49▪].

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SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITION AND THE POTENTIAL FOR RENAL PROTECTION IN HUMAN CLINICAL TRIALS

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 [54]. 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 [56].

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 [57], 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 [60]. Dapagliflozin also reduced eGFR acutely in conjunction with albuminuria, followed by the maintenance of stable renal function over 104 weeks of subsequent treatment [60]. 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 [32]. As uric acid lowering may be renal protective [61], the consistent decline in uric acid reported with SGLT2 inhibitors may be clinically significant.

FIGURE 2

FIGURE 2

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THE SALT PARADOX, RENAL FUNCTION AND SODIUM–GLUCOSE COTRANSPORTER-2 INHIBITION IN DIABETES

In addition to being implicated in the pathogenesis of hyperfiltration in T1D, increased SGLT2 activity may be involved in the renal response to changes in the dietary sodium intake and the pathogenesis of the so-called ‘salt-paradox’, whereby low dietary sodium intake causes a paradoxical increase in GFR [62,63]. In contrast, renal function remains stable under low dietary sodium in animals and humans [62,63]. As described in detail elsewhere, the maintenance of stable GFR under different dietary sodium conditions in nondiabetic conditions is likely the result of a balance between the primary vascular changes mediated by neurohormonal pressure–natriuresis pathways on one hand and the primary tubular factors (tubuloglomerular feedback) on the other hand [63]. In contrast, in diabetes, because of upregulation of SGLT2 activity, tubular forces tend to predominate, leading to the salt paradox. As a result of increased SGLT2 activity in diabetes mellitus, proximal tubular reabsorption becomes more sensitive to the changes in dietary sodium [63]. Therefore, when streptozotocin-diabetic animals are placed on a low sodium diet, less sodium is delivered to the proximal tubule, which avidly reabsorbs sodium with glucose, thereby exaggerating the decline in macula densa sodium delivery and adenosine release, causing pronounced afferent vasodilatation and a paradoxical increase in renal blood flow and GFR [40,63] – an observation that has been replicated in patients with T1D [64]. As a result of the unexpected direction of the effect of sodium restriction on GFR, the phenomenon has been referred to as the salt paradox of diabetes.

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 [64]. 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 [65]. 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.

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CONCLUSION

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 [66]. 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 [67]. 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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Acknowledgements

None.

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Financial support and sponsorship

D.Z.I.C. was supported by the Kidney Foundation of Canada Scholarship and a Canadian Diabetes Association-KRESCENT Program Joint New Investigator Award, and received operating support from the Heart and Stroke Foundation of Canada, the Kidney Foundation of Canada (KFOC) and the Canadian Institutes of Health Research (CIHR).

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Conflicts of interest

D.Z.I.C. has acted as a consultant for Boehringer Ingelheim, Janssen, Astellas and Merck, and has received speaker honoraria from Boehringer Ingelheim and Janssen and operational grant support from Boehringer Ingelheim and Eli Lilly. M.S. has no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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A large clinical trial showing that combination therapy of ACE inhibitor and ARB is associated with increased risk of adverse events in patients with diabetic nephropathy. Combined with data from ONTARGET and ALTITUDE, this study reinforced the risk associated with dual RAAS blockade.

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A meta-analysis of empagliflozin use in type 2 diabetes, with an excellent overview of the clinical effects.

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This first-in-class study demonstrated the effect of SGLT2 inhibition on metabolic and glycemic factors in patients with type 1 diabetes.

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Building on the previous genetic knockout work, this study demonstrated an important GFR-lowering effect with empagliflozin that was independent of glycemic effects. Antiproteinuric effects of SGLT2 inhibition were also reported in this study, a finding that has subsequently been replicated in the human clinical trials.

45. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells – renoprotection in diabetic nephropathy? PLoS One 2013; 8:e54442.
46▪. Tahara A, Kurosaki E, Yokono M, et al. Effects of sodium–glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol 2014; 66:975–987.doi: 10.1111/jphp.12223. [Epub ahead of print].

This mechanistic study using the SGLT2 inhibitor ipragliflozin demonstrated declines in oxidative stress and proinflammatory pathways in vivo in the rat model of type 1 diabetes.

47. Osorio H, Coronel I, Arellano A, et al. Sodium–glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid Med Cell Longev 2012; 2012:542042.
48. Arakawa K, Ishihara T, Oku A, et al. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)–glucose cotransporter inhibitor T-1095. Br J Pharmacol 2001; 132:578–586.
49▪. Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol 2014; 307:F317–F325.doi: 10.1152/ajprenal.00145.2014. [Epub ahead of print].

Along with the in-vitro work published by others, this mechanistic study's characterization of potential nephroprotective effects with SGTL2 inhibition provides a compelling basis for human investigation.

50. Cherney DZ, Miller JA, Scholey JW, et al. The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes. Diabetes 2008; 57:688–695.
51. Cherney DZI, Reich HN, Jiang S, et al. Hyperfiltration and effect of nitric oxide inhibition on renal and endothelial function in humans with uncomplicated type 1 diabetes mellitus. Am J Physiol Regul Integr Comp Physiol 2012; 303:R710–R718.
52. Cherney DZ, Konvalinka A, Zinman B, et al. Effect of protein kinase C beta inhibition on renal hemodynamic function and urinary biomarkers in humans with type 1 diabetes: a pilot study. Diabetes Care 2009; 32:91–93.
53▪▪. Cherney DZI, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129:587–597.

In this clinical study involving patients with type 1 diabetes, empagliflozin treatment for 8 weeks attenuated glomerular hyperfiltration.

54. Skrtic M, Yang GK, Perkins BA, et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia 2014; 57:2599–2602.doi: 10.1007/s00125-014-3396-4. [Epub ahead of print].
55▪▪. Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013; 15:853–862.

This randomized clinical trial in type 2 diabetes patients showed that the diuretic effects of SGLT2 inhibition lead to a contracted plasma volume that persists, leading to blood pressure lowering. In contrast, thiazide diuretic use caused transient volume contraction, suggesting that different mechanisms are responsible for antihypertensive effects with these two agents.

56. Cherney DZI, Perkins BA, Soleymanlou N, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int 2014; 86:1057–1058.doi: 10.1038/ki.2014.246.
57. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes therapy in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; 2:369–384.doi: 10.1016/S2213-8587(13)70208-0. [Epub ahead of print].
58. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 noninferiority trial. Lancet 2013; 382:941–950.
59▪▪. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013; 15:463–473.

This placebo-controlled clinical trial showed the persistent beneficial effects on glycemic control of canagliflozin in type 2 diabetes patients with chronic kidney disease. Moreover, similar to the observations made by others (Ref. [60]), SGLT2 inhibition acutely lowers eGFR, followed by stable long-term renal function. This pattern suggests an acute lowering of intraglomerular pressure, which may be protective.

60. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014; 16:147–158.doi: 10.1111/dom.12188. [Epub ahead of print].
61. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010; 5:1388–1393.
62. Vallon V, Huang DY, Deng A, et al. Salt-sensitivity of proximal reabsorption alters macula densa salt and explains the paradoxical effect of dietary salt on glomerular filtration rate in diabetes mellitus. J Am Soc Nephrol 2002; 13:1865–1871.
63. Vallon V, Blantz RC, Thomson S. Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol 2003; 14:530–537.
64. Miller JA. Renal responses to sodium restriction in patients with early diabetes mellitus. J Am Soc Nephrol 1997; 8:749–755.
65. Holtkamp FA, de Zeeuw D, Thomas MC, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011; 80:282–287.
66. Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010; 21:527–535.
67. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009; 361:40–51.
Keywords:

blood pressure; diabetic nephropathy; hyperfiltration; proteinuria; SGLT2 inhibition; tubular hypothesis

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