effects of sodium glucose co-transporter 2 inhibitors on the...

https://doi.org/10.1177/1479164118783756

Diabetes & Vascular Disease Research 1 –12© The Author(s) 2018Reprints and permissions: sagepub.co.uk/journalsPermissions.navDOI: 10.1177/1479164118783756journals.sagepub.com/home/dvr

Introduction

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are antihyperglycemic medications with effects that extend well beyond glycaemic control. Canagliflozin, dapagliflozin, and empagliflozin are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in patients with type 2 diabetes mellitus (T2DM), and ertugliflozin is in Phase IIIb of clinical inves-tigation, as is sotagliflozin – a dual SGLT 1 and 2 inhibitors. As the name implies, this class of medications works by tar-geting Na⁺/glucose cotransporter 2 located in the S1 seg-ment of the proximal tubule, inhibiting reabsorption of filtered glucose and thereby increasing glucosuria and low-ering plasma glucose independently of insulin. Pooled data from several phase II/IIIa studies have shown that canagli-flozin, dapagliflozin and empagliflozin lower glycated hae-moglobin (HbA1c) when used as a monotherapy or in combination with metformin, sulfonylureas, inhibitors of dipeptidyl peptidase 4 (DPP4i), glucagon-like peptide-1

receptor agonists (GLP-1RA) or insulin.1–5 These medica-tions are associated with negligible risk of hypoglycaemia, except for small incremental risks when used in

Effects of sodium glucose co-transporter 2 inhibitors on the kidney

Natalia de Albuquerque Rocha1,2, Ian J Neeland1,2, Peter A McCullough3, Robert D Toto1,4,5 and Darren K McGuire1,2,4

AbstractSodium–glucose cotransporter 2 inhibitors are antihyperglycaemic medications with an emerging evidence base for cardiovascular and kidney disease risk reduction. Sodium–glucose cotransporter 2 inhibitors medications lower plasma glucose by inhibiting glucose reabsorption in the proximal tubule of the kidney independent of insulin. Furthermore, they reduce intraglomerular pressure by restoring tubuloglomerular feedback. Large cardiovascular outcome trials of both empagliflozin and canagliflozin have consistently shown beneficial kidney effects that go beyond glycaemic control, such as reducing risk for incident nephropathy and progression of chronic kidney disease. The mechanisms by which sodium–glucose cotransporter 2 inhibitors improve kidney outcomes are not clear.

Proposed hypotheses underpinning the kidney benefits include kidney-specific effects such as decreased intraglomerular pressure, activation of angiotensin-(1-7) and the Mas receptor leading to decreased inflammation, decrease in overall kidney oxygen consumption, rise in erythropoietin levels, inhibition of the renal sodium–hydrogen exchanger and secondary kidney effects related to improvements in HbA1c and blood pressure.

This review will focus on describing the mechanisms of action of sodium–glucose cotransporter 2 inhibitors in the kidney, clinical efficacy data on their use in patients with chronic kidney disease, postulated physiologic underpinnings of kidney protection observed with sodium–glucose cotransporter 2 inhibitors and the promise and potential pitfalls for their use in patients with chronic kidney disease.

KeywordsSodium–glucose cotransporter 2 inhibitors, kidney, type 2 diabetes mellitus, sodium–glucose cotransporter 2 inhibitors, empagliflozin, canagliflozin, chronic kidney disease

1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

2 Department of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

3 Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX, USA

4 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

5 Department of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Corresponding author:Natalia de Albuquerque Rocha, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8830, USA. Email: [email protected]

783756 DVR0010.1177/1479164118783756Diabetes & Vascular Disease Researchde Albuquerque Rocha et al.research-article2018

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combination with sulfonylureas and insulin.2,6–8 In addition, phase III efficacy and safety trials have shown significant decreases in body weight2,6,9,10 and systolic blood pressure (SBP)6,11 at the expense of a small increase in risk of devel-oping urinary tract infections and a modest incremental risk for genital mycotic infections in patients using these medi-cations.2,12,13 In addition, canagliflozin was shown in the CANVAS Programme to double the risk of lower limb amputation when compared with placebo, a finding not yet amply elucidated. Similarly, a numerical imbalance in rates of bladder cancer between treatment groups during the new drug application to the FDA for dapagliflozin was noted and this issue is being prospectively evaluated. The CREDENCE (canagliflozin, NCT02065791) and DECLARE (dapagliflo-zin, NCT01730534) trials are expected to help clarify these safety concerns.

Cardiovascular (CV) outcome trials of both empagliflo-zin and canagliflozin have consistently shown beneficial effects that go beyond glycaemic control. The EMPA REG OUTCOME trial was a randomized, controlled clinical trial comparing the effect of empagliflozin versus placebo on CV outcomes in patients with established atheroscle-rotic CV disease, demonstrating superiority of empagliflo-zin.14 Empagliflozin also significantly reduced the risk for the composite outcomes of CV mortality, all-cause mortal-ity and hospitalizations for heart failure.

In consonance, results of the CANVAS and CANVAS-R trials have been published in combination as the CANVAS Programme,15 pooling data from over 10,000 participants randomized to canagliflozin or placebo, demonstrating superiority of canagliflozin for major adverse CV events (Table 1).

Less is known about the long-term kidney effects of SGLT2i. Below, we focus on describing the mechanisms of action of SGLT2i in the kidney, clinical efficacy data on their use in patients with chronic kidney disease (CKD), postulated physiologic underpinnings for kidney protec-tion observed with SGLT2i and potential and pitfalls for their use in patients with CKD.

Kidney effects of SGLT2i medications: observations from large-scale outcome trials

The long-term effects of empagliflozin on kidney out-comes were part of secondary prespecified analyses of the EMPA REG OUTCOME trial.16 Patients with T2DM and estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m2 were randomized to receive either empagliflozin 10 mg, 25 mg or placebo once daily. The measured kidney outcomes included incident albuminuria and incident or worsening nephropathy, which was defined as progression to incident microalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or death from kidney disease. The authors found a 39%

lower risk of nephropathy incidence and progression with empagliflozin (both arms pooled) versus placebo [hazard ratio (HR): 0.61; 95% confidence interval (CI): 0.53 to 0.70; p < 0.001] and a 46% reduction in the composite kid-ney outcome of doubling of serum creatinine, initiation of renal replacement therapy or death due to kidney disease (HR: 0.54; 95% CI: 0.40 to 0.75; p < 0.001). Patients in the empagliflozin group also had a significantly lower risk of progression from micro- to macroalbuminuria, although no significant between-group difference in the rate of inci-dent albuminuria was reported. Patients in the empagliflo-zin group had a small decrease in eGFR after starting the drug, with a similar pattern observed in patients with eGFR of ⩾60 mL/min/1.73 m2 and

de Albuquerque Rocha et al. 3

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30% of the participants had albuminuria at baseline and the mean eGFR was 76.5 mL/min/1.73 m2, demonstrating a low kidney-risk group. Unlike empagliflozin, however, the CV and kidney benefits with canagliflozin came at the cost of a doubling of risk of amputations associated with canagliflozin versus placebo (6.3 vs 3.4 participants per 1000 patient-years; HR: 1.97; 95% CI: 1.41 to 2.75; Figure 1, Table 3). Although mechanistic explorations are not the objective of clinical outcome trials, these results are

provocative and further studies in populations with CKD both with and without diabetes are underway (such as the EMPRESS trial with empagliflozin).19

The kidney as the gatekeeper of SGLT2 inhibitor efficacy

The beneficial effects of SGLT2i medications rely pro-foundly on kidney function. In a healthy patient without

Figure 1. Kaplan–Meier estimates depicting the effects of (a) empagliflozin and (b) canagliflozin on composite kidney outcomes from the EMPA-REG OUTCOME trial and the integrated Canvas Programme, respectively (adapted from REG OUTCOME16 and CANVAS Programme15). Doubling of serum creatinine on the EMPA-REG OUTCOME represents a 57% drop in eGFR.


diabetes, virtually all glucose filtered at the glomerulus is reabsorbed in the proximal tubule, up to limit of about 180 mg/dL. Above this level, the maximal reabsorptive capacity of the kidneys (tubular max for glucose, TmG) is achieved and excess glucose is excreted in the urine. In this setting, SGLT2 is responsible for most of the reabsorp-tion (80%–90%) and SGLT1, located more distally in the tubule, absorbs the remainder (10%–20%). In patients with diabetes, SGLT2 expression and capacity are para-doxically increased in the proximal tubule by mechanisms not yet fully understood,22,23 increasing TmG by as much as 20%.24,25 Consequently, in diabetes, a vicious cycle is cre-ated with an increase in the capacity of the kidneys to reab-sorb urinary glucose, maintaining and even exacerbating hyperglycaemia.

In patients without diabetes, glomerular filtration is steadily maintained, despite variations in blood pressure and plasma volume, by modulation of pre-glomerular (afferent) and post-glomerular (efferent) arteriolar tone in response to vasoactive mediators and the tubuloglomerular feedback (TGF) mechanism. This balance is disrupted by hyperglycaemia in patients with diabetes, with increased proximal glucose reabsorption coupled with increased proximal sodium reabsorption via SGLT2 and reduced

sodium (and chloride) delivery to the macula densa, mim-icking kidney hypoperfusion. This leads to stimulation of the TGF mechanism affecting afferent arteriolar dilation, as well as efferent arteriolar constriction via other path-ways, resulting in increased intraglomerular pressure (i.e. glomerular hypertension) and hyperfiltration, both of which have been implicated in the genesis and progression of CKD in diabetes.26–30 With SGLT2i, the reabsorption of glucose and sodium is decreased in the proximal tubule, and as a consequence, more sodium is delivered to the macula densa restoring normal TGF tone, reversing affer-ent artery dilation, reducing intraglomerular pressure and decreasing hyperfiltration and single nephron GFR. Of note, this decline in GFR is a hemodynamic phenomenon (similar to that seen with ACE inhibitors and ARBs) and does not reflect glomerular/kidney injury or pathologic change in GFR.

Thus, SGLT2i medications are mechanistically able to acutely improve glycaemic control and decrease glomeru-lar hyperfiltration.31–33 Concurrently, SGLT2i causes a natriuretic and osmotic diuretic effect and resultant con-traction in plasma volume. It is estimated that SGLT2i can reduce plasma volume by about 7% due to the diuretic effects, which in contrast to the effects of thiazides where

Table 2. Renal outcomes found on the EMPA-REG (1) outcome trial.

EMPA-REG trial

Annualized event rate with drug vs placebo (rate/1000 patient-years)

Hazard ratio (95% CI) p value

Incident or worsening nephropathy 12.7 versus 18.8 0.61 (0.53–0.70)


plasma volume effects are short-lived during chronic treat-ment, a plasma volume reduction that remains relatively constant during exposure to SGLT2i medications.11

Phase III trials have consistently shown small, but sig-nificant decreases in SBP and diastolic blood pressure (DBP) with SGLT2i medications,6,11 which may also help maintain kidney function over time. The exact mecha-nisms by which SGLT2i medications lower blood pressure remains a matter of debate, but cannot be attributed to their diuretic effects. This is best demonstrated by the consistent observation of greater BP reductions associated with decreasing eGFR for all SGLT2i medications,26,34 even when adjusting for baseline blood pressure and in the set-ting of diminishing effects with waning eGFR for changes in HbA1c. The effect of SGLT2i medications on SBP and DBP is fairly constant across the class and is not altered by background anti-hypertensive medications.34,35 SGLT2i medications have a moderate diuretic effect, leading to both acute and sustained intravascular volume contrac-tion.11,26,36–38 Interestingly, this effect is not followed by a compensatory increase in heart rate, displaying possible indirect evidence for inhibition of sympathetic nervous system activity, perhaps as a downstream effect of restora-tion of normal TGF activity. The impact of weight loss on long-term BP reduction with this class of medications has been estimated to be around 30%–40%,39–41 indicating that although significant, it is not the most prominent contribu-tor. Furthermore, studies have shown that the decrease in BP with SGLT2i is observed significantly earlier than the observed weight reduction, suggesting that weight loss might have a latent effect on BP, but not an acute effect.35

Mechanisms of kidney protection

The mechanisms by which empagliflozin and canagliflo-zin impact kidney outcomes are not fully understood. Several hypotheses have been proposed, including better BP control, improvement in HbA1c, decreased glomerular hyperfiltration and/or glomerular hypertension, weight reduction, an overall decrease in renal oxygen consump-tion, shift in renal metabolism from free fatty acid to ketone use (which is a more efficient metabolic sub-strate),42 inhibition of sodium hydrogen exchanger and possibly an increase in erythropoietin production by spe-cial fibroblasts located at the juxtamedullary apparatus resulting in increased red-cell mass and oxygen-carrying capacity (Figure 2). The small but significant decrease in BP with SGLT2i medications is unlikely to fully explain the robust beneficial effects on kidney outcomes, espe-cially in the context of a very high prevalence of back-ground ACE inhibitor/ARB therapy in the Cardiovascular Outcome Trials (CVOTs) reported to date. Similarly, improvements in glucose control is an unlikely explana-tion given the fact that historically, improvements in meas-ures of kidney health associated with intensification of

glucose control have taken a decade or more to manifest,43 and kidney benefits were evident as early as three months in EMPA REG OUTCOME. A pooled analysis comprising patients with T2DM who participated in one of five phase III trials with empagliflozin found overall improvements in microalbuminuria (–32%) and macroalbuminuria (–41%), which was only partially (~50%) explained by changes in HbA1c, weight and BP, variables known to be associated with albuminuria.44

The kidney protection observed in the EMPA REG OUTCOME study and CANVAS programme, where roughly 80% of patients were on background ACE/ARB in addition to SGLT2i versus placebo, may be explained by a shift to the non-classical renin–angiotensin–aldoster-one system (RAAS) pathway (Figure 3).45 Studies have shown an increase in circulating RAAS mediators such as renin, angiotensin II and aldosterone with SGLT2i,11,39 perhaps due to natriuresis and volume depletion. RAAS functions via two possible pathways. The classical path-way leads to the production of angiotensin II and activa-tion of the AT1 receptor with consequent glomerular efferent artery vasoconstriction, sodium retention and inflammation, cell proliferation, fibrosis and apoptosis in pathologic conditions.46 ACE inhibitors and ARBs act on this pathway and are known to confer kidney protection by preventing efferent artery constriction, subsequently reducing diabetic hyperfiltration. The non-classical RAAS pathway is thought to oppose the actions of the angiotensin II-AT1 receptor axis, contributing to the thera-peutic effects of blockade of the classical pathway. The non-classical axis relies on ACE2 to produce angioten-sin-(1-7), which activates the Mas receptor, leading to systemic arteriolar vasodilation, natriuresis, diuresis, reduced oxidative stress and antiproliferative activity by means of nitric oxide and prostaglandin upregulation.46–48 In addition, through the Mas receptor, angiotensin-(1-7) has been shown to reduce signalling pathways thought to be responsible to fibrogenesis and chronic inflamma-tion.49 Animal studies have shown an additive benefit of SGLT2i to angiotensin-converting enzyme inhibitors (ACEi) in slowing the progression of diabetic nephropa-thy50 and lowering BP,51–53 an effect that might be linked to upregulation of the non-classical pathway.

Another hypothesis that has been proposed to explain the improved kidney outcomes with SGLT2i relies on the optimization of kidney oxygen consumption and shifts in substrate energetics42 away from energy-inefficient meta-bolic substrates such as free fatty acids and towards ‘super fuels’ such as ketone bodies. Based on the TGF mecha-nism described previously, GFR is increased in diabetes leading to high luminal sodium and glucose concentrations and a resulting excess of proximal tubule intracellular sodium, activation of the Na+/K+ATPase pump and conse-quent increase in kidney oxygen consumption (QO2).54,55 In a study utilizing a rat single-nephron model, chronic


SGLT2 inhibition lowered renal cortical QO2 by about 30%. However, due to a consequent increase in sodium reabsorption by SGLT1 located at the S3 segment, QO2 at the renal medulla was increased by 26%.56 Interestingly, the reduction in filtration rate and its impact in lowering paracellular and transcellular sodium reabsorption in the proximal tubule more than counterbalance the upstream increase in QO2, leading to an overall positive balance. It is plausible that the substantial decrease in overall kidney QO2 leads to less hypoxic stress and could lead to long-term beneficial kidney effects.42

The outer medulla of the kidney is an area susceptible to ischaemic injury due to the lower oxygen tension found in this area when compared to the cortex. As mentioned above, SGLT2 inhibition leads to an increase in QO2 at the kidney inner cortex/outer medulla level due to an increase

in SGLT1 activity. Knowing that renal hypoxia is consid-ered one of the mechanisms leading to CKD, this finding can be worrisome. However, chronic SGLT2 blockade with empagliflozin and canagliflozin did not translate into worse kidney outcomes as would be expected with medul-lary hypoxic injury. It is hypothesized, but not yet fully explored, that this rise in QO2 by the outer renal medulla is balanced by increased beta-hydroxybutyrate (BHOB) metabolism in that region. This might be a simplistic explanation as substrate metabolism in the kidney is com-plex and involves different substrate sources depending on fasting or fed state as well as substrate availability. It is known that all regions of the renal tubule are capable of metabolizing ketone bodies, specially under high plasma concentration57 (such as noted with SGLT2 inhibition).58 Further studies are needed to precisely measure kidney

Figure 2. Potential mechanisms underpinning the kidney-specific benefits of SGLT2i.BP: blood pressure; SGLT2i: sodium glucose cotransporter 2 inhibitor; RAAS: renin angiotensin aldosterone system; ACE2: angiotensin converting enzyme type 2; NHE: sodium–hydrogen exchanger.


glucose, ketone bodies and free fatty acid utilization in the setting of SGLT2 inhibition.

Another possible explanation is that this increase in QO2 at the corticomedullary junction could lead to a decrease in renal cortical oxygen tension and therefore be the stimulus for the production of erythropoietin as has been reported in two recent studies. An unexpected rise in haematocrit (out of proportion to the degree of plasma volume contraction) with empagliflozin observed in the EMPA REG OUTCOME trial raised the possibility that increased oxy-gen carrying capacity and oxygen supply to both myocar-dium and to kidney could contribute to the beneficial effects observed in the trial.59 Similar observations have been made with dapagliflozin.11 Exposure to dapagliflozin was accompanied by a transient increase in reticulocyte and serum erythropoietin levels, with erythropoietin levels returning to stable baseline in the context of a ‘reset’ increased haematocrit. These observations have engen-dered the hypothesis that SGLT2i can directly increase red cell mass by enhancement of erythropoiesis. It is important

to note that red blood cell mass was not directly measured in any of the prior studies, and these findings have not been reproduced to date. Nevertheless, this idea highlights the concept of the kidney possessing a ‘critmeter’ located in the juxtamedullary region, in which erythropoietin pro-duction is triggered by changes in oxygen tension and may be affected by SGLT2 inhibition.60 Furthermore, based on experimental studies in rats and mice in which erythropoi-etin was shown to directly protect podocytes from diabetic nephropathy damage, it is possible that erythropoietin can not only be a mediator of erythrocytosis and modulator of red cell mass, but also one of the mediators of direct kid-ney protection caused by SGLT2i.61,62 The relevance of the increase in oxygen consumption by the outer medulla and clinical impact of the rise in erythropoietin level is yet to be fully explored.

Finally, another recently proposed theory to explain the kidney benefits of SGLT2i is based on the known interac-tion between SGLT2 and the sodium–hydrogen exchanger (NHE). The isoforms NHE1 and NHE3 are present in the

Figure 3. Potential explanation for kidney protection with SGLT2i when combined with ACEi/ARB by favouring activation of AT2 and Mas receptors. SGLT2i lead to natriuresis and volume depletion that activate the RAAS system. When ACEi is present, ACE2 predominates, leading to the formation of angiotensin 1–7 and activation of the MAS receptor.SGLT2: sodium glucose cotransporter 2; ACE: angiotensin-converting enzyme; ACE2: angiotensin-converting enzyme 2; AT1: type 1 angiotensin II receptor; AT2: type 2 angiotensin II receptor.


kidneys, and their expression is increased by hyperglycae-mia and hyperinsulinemia. Both isoforms of NHE contrib-ute to the known features of diabetic nephropathy such as hyperfiltration, sodium reabsorption and mesangial cell proliferation63 and their increased activity is related to vas-cular injury associated with hyperglycaemia.64,65 Kidney NHE activity is increased in patients with heart failure, possibly contributing to diuretic resistance. In vitro studies in proximal tubule cells have demonstrated an overexpres-sion of NHE1 in the setting of high glucose followed by pH dysregulation and that inhibition of NHE1 restores pH and decreases cell apoptosis induced by high glucose. Furthermore, inhibition of NHE1 by cariporide was shown to normalize the redox status induced by advanced glyca-tion end products (AGE) and prevented glomerular fibro-sis.65 Importantly, both NHE1 and NHE3 expression in the kidney are upregulated by angiotensin II receptor type 1 and agonism of type 2 receptors inhibits NHE activity.63 Thus, it is hypothesized that such as with inhibitors of the rennin–angiotensin–aldosterone system, SGLT2i may decrease NHE expression and activity in the kidney, con-tributing to decreased hyperfiltration and attenuating the related fibrotic and proliferative action.63

Promises and pitfalls of SGLT2i use in patients with CKD

The EMPA REG OUTCOME trial and the CANVAS Programme showed no heterogeneity of effect in the pri-mary outcome of MACE, CV death, heart failure and all-cause mortality among patient subgroups stratified by normal kidney function versus those with CKD. Both trial programmes also showed consistent kidney protec-tive effects in participants with baseline CKD when com-pared with individuals with normal kidney function.14,15 This raises the speculation of whether SGLT2i confers kidney protection independently of ambient glucose and GFR, which could potentially expand their use to patients with CKD without diabetes.66 In both trial programmes, the average baseline eGFR was within normal range (EMPA REG OUTCOME 74 mL/min/1.73 m2 and in CANVAS 76.5 mL/min/1.73 m2) and only one-third of patients had albuminuria at baseline, indicating that most patients had either mild kidney disease or normal kidney function. For this reason, the number of events ascer-tained in the assessment of kidney outcomes was very low in both trial programmes, and extrapolation of these effects to a more advanced kidney disease population may be premature. Further studies designed specifically for the CKD population are needed prior to concluding that SGLT2i should be used with the specific kidney pro-tection intent. Such studies are underway (e.g. the CREDENCE trial with canagliflozin-NCT02065791; the EMPRESS trial with empagliflozin;19 and the DAPA-CKD trial-NCT03036150).

Although SGLT2i shows promise in kidney protection, the antihyperglycemic mode of action is dependent on fil-tered glucose load. Consequently, the use of SGLT2i in patients with more advanced CKD is restricted by medica-tion product labels. In the United States, dapagliflozin is approved for use in patients with eGFR > 60 mL/min/1.73 m2, canagliflozin > 45 mL/min/1.73 m2 with dose adjustment for eGFR between 45 and 60, and empagliflo-zin > 45 mL/min/1.73 m2. The EMPA REG OUTCOME study and the CANVAS Programme have enrolled patients with lower eGFR (>30 mL/min/1.73 m2) with no evident kidney-related safety signals and with important improve-ments in blood pressure, kidney and CV outcomes despite smaller changes in HbA1c in the subgroups with compro-mised kidney function, supporting optimism that these medications might be accessible to CKD patients in the future. A recent subgroup analysis with participants with GFR < 60 of the EMPA-REG OUTCOME study showed that the beneficial outcomes of empagliflozin were no dif-ferent from those with normal baseline kidney function and that the adverse event profile was also similar.67 The CREDENCE trial (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Established Diabetic Nephropathy – NCT02065791) and the DAPA-CKD trial (NCT03036150) will hopefully elucidate key clinical kidney effects of canagliflozin and dapagliflozin (Table 1), as they both have kidney primary composite outcomes. Both are expected to publish results in 2020. Kidney effects of dual SGLT1/2 inhibition with sotagliflozin, currently in CVOT development, will be evaluated in the SCORED clinical trial (NCT03315143).

The FDA issued a warning in June 2016 intensifying the previous labelled warnings about the risk of acute kid-ney injury (AKI) in patients using canagliflozin or dapagli-flozin (but not empagliflozin). This warning states that from March 2013 to October 2015, the FDA has received reports of over 100 confirmable cases of AKI, with approx-imately half of them occurring within 1 month of starting the drugs. Some cases required hospitalization and dialysis and most showed improvement in kidney function after discontinuation of the medication. Some of the reported cases involved patients who were concomitantly taking other drugs known to affect kidney function and some had signs of dehydration. This warning did not include any AKI cases involving patients taking empagliflozin.

Conclusion

The SGLT2is have emerged as paradigm-shifting medica-tions in the modern type 2 diabetes era. Their kidney pro-tection outcomes, on the backdrop of best available evidence-based treatment, are unprecedented and seem to be a class-wide effect. Further studies with prespecified kidney endpoints as primary outcomes are in progress and


will help clarify the effects and safety of SGLT2is in patients with CKD. Questions remain as to whether their GFR-independent effects leading to decreased hyperfiltra-tion and intraglomerular pressure would benefit patients without diabetes. Studies such as the DAPA-CKD (NCT03036150), EMPEROR reduced (NCT03057977) and EMPEROR preserved (NCT03057951)68,69 are recruit-ing patients with and without diabetes and have changes in eGFR as a secondary outcome. Similarly, the EMPRESS trial will recruit patients with CKD, with and without dia-betes, to be randomized to treatment with empagliflozin versus placebo.19 These trials will explore the hypothesis of kidney protection in the absence of diabetes and open the scenario for alternative uses of SGLT2i.

Author’s contributions

NDAR, PAM, IJN, RDT and DKM have contributed with data interpretation, manuscript writing and editing for intellectual content.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

Dr Neeland is supported by grant K23DK106520 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health and by the Dedman Family Scholarship in Clinical Care from UT Southwestern.

Relationship with industry

N.D.A.R. and P.A.M. have nothing to disclose. I.J.N. has received research support from Boehringer Ingelheim. R.D.T. has served as an advisor or consultant for Amgen, Inc.; AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Relypsa, Inc.; ZS Pharma; Novo Nordisk, Inc; Bayer Inc and Reata Pharmaceuticals, Inc. D.K.M. has received support for clinical trial leadership from AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline and Esperion and honoraria for consultancy from AstraZeneca, Sanofi Aventis, Lilly US, AstraZeneca, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk and Metavant.

Search strategy and selection criteria

References for this review were identified through searches of PubMed for articles published from 1980 to 2017 by use of the terms ‘SGLT2 inhibitors’, ‘Empagliflozin’, ‘Canagliflozin’ and ‘Dapagliflozin’ in combination to the term ‘diabetes’, ‘kidney’ and ‘renal’. Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles pub-lished in English were included.

References

1. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin ver-sus glipizide as add-on therapy in patients with type 2 diabe-

tes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34: 2015–2022.

2. Nauck MA. Update on developments with SGLT2 inhibi-tors in the management of type 2 diabetes. Drug Des Devel Ther 2014; 8: 1335–1380.

3. Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract 2012; 66: 446–456.

4. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabe-tes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013; 382: 941–950.

5. Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 2013; 36: 4015–4021.

6. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a sys-tematic review and meta-analysis. Ann Intern Med 2013; 159: 262–274.

7. Clar C, Gill JA, Court R, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabe-tes. BMJ Open 2012; 2: e001007.

8. Berhan A and Barker A. Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials. BMC Endocr Disord 2013; 13: 58.

9. Neeland IJ, McGuire DK, Chilton R, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2016; 13: 119–126.

10. Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 2014; 16: 159–169.

11. LambersHeerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic prop-erties in subjects with type 2 diabetes. Diabetes Obes Metab 2013; 15: 853–862.

12. Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagli-flozin. J Diabetes Complications 2013; 27: 479–484.

13. Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflo-zin. J Diabetes Complications 2013; 27: 473–478.

14. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, car-diovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–2128.

15. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–657.

16. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–334.

17. Rajasekeran H, Lytvyn Y and Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction


in patients with type 2 diabetes: the emerging role of natriu-resis. Kidney Int 2016; 89: 524–526.

18. Toto RD. SGLT-2 inhibition: a potential new treatment for diabetic kidney disease? Nephron 2017; 137: 64–67.

19. Boehringer Ingelheim and Eli Lilly and Company. Empagliflozin (Jardiance®) to be studied in chronic kid-ney disease. 2017, https://www.boehringer-ingelheim.com/press-release/empagliflozin-be-studied-chronic-kidney-dis-ease

20. Janssen Research & Development, LLC. Evaluation of the effects of canagliflozin on renal and cardiovascu-lar outcomes in participants with diabetic nephropathy (CREDENCE). Bethesda, MD: U.S. National Library of Medicine, 2000.

21. AstraZeneca. A study to evaluate the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (Dapa-CKD). Bethesda, MD: U.S. National Library of Medicine, 2000.

22. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med 2015; 66: 255–270.

23. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in pro-portion to hyperglycemia and prevents glomerular hyperfil-tration in diabetic Akita mice. Am J Physiol Renal Physiol 2014; 306: F194–F204.

24. Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest 1971; 28: 101–109.

25. Farber SJ, Berger EY and Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest 1951; 30: 125–129.

26. Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glu-cose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mech-anisms, and clinical applications. Circulation 2016; 134: 752–772.

27. Sasson AN and Cherney DZ. Renal hyperfiltration related to diabetes mellitus and obesity in human disease. World J Diabetes 2012; 3: 1–6.

28. Vallon V, Richter K, Blantz RC, et al. Glomerular hyper-filtration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 1999; 10: 2569–2576.

29. Zatz R, Meyer TW, Rennke HG, et al. Predominance of hemodynamic rather than metabolic factors in the pathogen-esis of diabetic glomerulopathy. Proc Natl Acad Sci U S A 1985; 82: 5963–5967.

30. Thomson SC, Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular func-tion in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 2012; 302: R75–R83.

31. Roden M, Weng J, Eilbracht J, et al. Empagliflozin mono-therapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2013; 1: 208–219.

32. Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in

patients with type 2 diabetes: a 24-week, randomized, dou-ble-blind, placebo-controlled trial. Diabetes Care 2013; 36: 3396–3404.

33. 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.

34. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hyper-tension. Diabetes Care 2015; 38: 420–428.

35. Oliva RV and Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens 2014; 8: 330–339.

36. Inzucchi SE, Zinman B, Fitchett D, et al. How does empa-gliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018; 41: 356–363.

37. Kawasoe S, Maruguchi Y, Kajiya S, et al. Mechanism of the blood pressure-lowering effect of sodium-glucose cotrans-porter 2 inhibitors in obese patients with type 2 diabetes. BMC Pharmacol Toxicol 2017; 18: 23.

38. Sha S, Polidori D, Heise T, et al. Effect of the sodium glu-cose co-transporter 2 inhibitor canagliflozin on plasma vol-ume in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2014; 16: 1087–1095.

39. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhi-bition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587–597.

40. Cefalu WT, Stenlöf K, Leiter LA, et al. Effects of cana-gliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia 2015; 58: 1183–1187.

41. Sjöström CD, Hashemi M, Sugg J, et al. Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels. Diabetes Obes Metab 2015; 17: 809–812.

42. Mudaliar S, Alloju S and Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care 2016; 39: 1115–1122.

43. Scheen AJ and Delanaye P. Effects of reducing blood pres-sure on renal outcomes in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Metab 2017; 43: 99–109.

44. Cherney DZ, Lund SS, Perkins BA, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflo-zin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia 2016; 59: 1860–1870.

45. Kawanami D, Matoba K, Takeda Y, et al. SGLT2 inhibitors as a therapeutic option for diabetic nephropathy. Int J Mol Sci 2017; 18: E1083.

46. Chappell MC. Nonclassical renin-angiotensin system and renal function. Compr Physiol 2012; 2: 2733–2752.

47. Burrell LM, Johnston CI, Tikellis C, et al. ACE2, a new reg-ulator of the renin-angiotensin system. Trends Endocrinol Metab 2004; 15: 166–169.

48. Mizuiri S and Ohashi Y. ACE and ACE2 in kidney disease. World J Nephrol 2015; 4: 74–82.

https://www.boehringer-ingelheim.com/press-release/empagliflozin-be-studied-chronic-kidney-diseasehttps://www.boehringer-ingelheim.com/press-release/empagliflozin-be-studied-chronic-kidney-diseasehttps://www.boehringer-ingelheim.com/press-release/empagliflozin-be-studied-chronic-kidney-disease


49. Padda RS, Shi Y, Lo CS, et al. Angiotensin-(1-7): a novel peptide to treat hypertension and nephropathy in diabetes? J Diabetes Metab 2015; 6: 615. doi:10.4172/2155-6156.1000615

50. Kojima N, Williams JM, Takahashi T, et al. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther 2013; 345: 464–472.

51. Kojima N, Williams JM, Slaughter TN, et al. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats. Physiol Rep 2015; 3: e12436.

52. Weber MA, Mansfield TA, Alessi F, et al. Effects of dapagliflo-zin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press 2016; 25: 93–103.

53. Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabe-tes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab 2016; 18: 590–597.

54. Körner A, Eklöf AC, Celsi G, et al. Increased renal metabo-lism in diabetes. Mechanism and functional implications. Diabetes 1994; 43: 629–633.

55. Layton AT, Vallon V and Edwards A. Predicted conse-quences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol 2016; 310: F1269–F1283.

56. Layton AT, Vallon V and Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol 2015; 308: F1343–F1357.

57. Guder WG, Wagner S and Wirthensohn G. Metabolic fuels along the nephron: pathways and intracellular mechanisms of interaction. Kidney Int 1986; 29: 41–45.

58. Mudaliar S, Polidori D, Zambrowicz B, et al. Sodium-glucose cotransporter inhibitors: effects on renal and intesti-nal glucose transport: from bench to bedside. Diabetes Care 2015; 38: 2344–2353.

59. Ferrannini E, Baldi S, Frascerra S, et al. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhi-bition in patients with type 2 diabetes. Diabetes Care 2017; 40: 771–776.

60. Dunn A, Lo V and Donnelly S. The role of the kidney in blood volume regulation: the kidney as a regulator of the hematocrit. Am J Med Sci 2007; 334: 65–71.

61. Ruester C, Franke S, Bondeva T, et al. Erythropoietin pro-tects podocytes from damage by advanced glycation end-products. Nephron Exp Nephrol 2011; 117: e21–e30.

62. Yanai H and Katsuyayama H. A possible mechanism for renoprotective effect of sodium-glucose cotransporter 2 inhibitor: elevation of erythropoietin production. J Clin Med Res 2017; 9: 178–179.

63. Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation 2017; 136: 1548–1559.

64. Shuang-Xi W, Li-Ying L, Hu M, et al. Na+/H+ exchanger inhibitor prevented endothelial dysfunction induced by high glucose. J Cardiovasc Pharmacol 2005; 45: 586–590.

65. Li P, Chen GR, Wang F, et al. Inhibition of NA+/H+ exchanger 1 attenuates renal dysfunction induced by advanced glycation end products in rats. J Diabetes Res 2016; 2016: 1802036.

66. Verma S, McMurray JJV and Cherney DZ. The metabolo-diuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure. JAMA Cardiol 2017; 2: 939–940.

67. Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mel-litus, established cardiovascular disease, and chronic kidney disease. Circulation 2018; 137: 119–129.

68. ClinicalTrials.gov. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced), https://clinicaltrials.gov/ct2/show/NCT03057977

69. ClinicalTrials.gov. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved), https://clinicaltrials.gov/ct2/show/NCT03057951

https://clinicaltrials.gov/ct2/show/NCT03057977https://clinicaltrials.gov/ct2/show/NCT03057977https://clinicaltrials.gov/ct2/show/NCT03057951https://clinicaltrials.gov/ct2/show/NCT03057951

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