Sodium–Glucose Cotransporter 2 Inhibition and DiabeticKidney DiseaseRadica Z. Alicic,1,2 Joshua J. Neumiller,3 Emily J. Johnson,1 Brad Dieter,1 and Katherine R. Tuttle1,2,4,5

Diabetes 2019;68:248–257 | https://doi.org/10.2337/dbi18-0007

Diabetic kidney disease (DKD) is now the principal causeof chronic kidney disease leading to end-stage kidneydisease worldwide. As a primary contributor to the ex-cess risk of all-cause and cardiovascular death in di-abetes, DKD is a major contributor to the progressivelyexpanding global burden of diabetes-associated mor-bidity and mortality. Sodium–glucose cotransporter2 (SGLT2) inhibitors are a newer class of antihypergly-cemic agents that exert glucose-lowering effects viaglycosuric actions. Preclinical studies and clinical trialsof SGLT2 inhibitors have consistently demonstratedreduction of albuminuria and preservation of kidneyfunction. In particular, SGLT2 inhibitors lower risk ofcongestive heart failure, a major cardiovascular compli-cation in DKD. This Perspective summarizes proposedmechanisms of action for SGLT2 inhibitors, integratesthese data with results of recent cardiovascular out-comes trials, and discusses clinical applications forpatients with DKD. The American Diabetes Association/European Association for the Study of Diabetes ConsensusReport published online in October 2018 recommendsSGLT inhibitors as preferred add-on therapy for patientswith type 2 diabetes and established cardiovasculardisease or chronic kidney disease, if kidney function isadequate. Results of the ongoing and just completedclinical trials conducted in patients with established DKDwill facilitate further refinement of current guidelines.

The impact of the current diabetes pandemic is rapidlyapproaching that of the Great Plague (1,2). Its prevalencehas nearly quadrupled since the 1980s, and 1 in 10 adults,or 642 million people worldwide, are now projected to havediabetes by the year 2040 (3). As the number of peopleliving with diabetes rises, the prevalence of diabetic

complications is also rapidly escalating. Approximatelyhalf of individuals with type 2 diabetes (T2D) and one-third of people with type 1 diabetes (T1D) develop diabetickidney disease (DKD), a microvascular complication that isnow the leading cause of chronic kidney disease (CKD) andend-stage kidney disease (ESKD) in the world (4–6).

For people with diabetes, development of kidney dis-ease increases the risk of death by five- to sixfold (7–9).Tragically, approximately 90% of patients with DKD diebefore requiring kidney replacement therapy (KRT).Among those who reach ESKD, the risk of death is 10-to 100-fold higher than for individuals with normal kidneyfunction (10). Depending on the country, only 10%–50%of those who need KRT will ever receive it (10). Thus, inmany parts of the world, ESKD equates to a virtual deathsentence (10–12). Although survival rates for patientsreceiving KRT have improved modestly over the pastfew decades, the increased risk of death remains unac-ceptably high, as one-third of those treated by mainte-nance dialysis die within 3 years of initiation (13).

Achieving glycemic control with conventional bloodglucose–lowering therapies early in the course of T1D orT2D reduces, but does not eliminate, the risk of developingDKD (11,14,15). Therefore, agents that control hypergly-cemia safely while also preventing or treating DKD areurgently needed. Over the past three decades, discoveryand elucidation of the role of sodium symporters in glu-cose reabsorption, and thereby glucose homeostasis, havepointed to sodium–glucose cotransporter 2 (SGLT2) in-hibition as a viable therapeutic target (16–19). In cardio-vascular disease (CVD) outcomes trials conducted forsafety, SGLT2 inhibitors actually have demonstrated clearbenefits on CVD and CKD. This Perspective highlights

1Providence Health Care, Washington State University, Spokane, WA2University of Washington School of Medicine, Seattle, WA3College of Pharmacy and Pharmaceutical Sciences, Washington State University,Spokane, WA4Kidney Research Institute, University of Washington, Seattle, WA5Institute of Translational Health Sciences, University of Washington, Seattle, WA

Corresponding author: Radica Z. Alicic, radica.alicic@providence.org

Received 13 August 2018 and accepted 7 November 2018

© 2019 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at http://www.diabetesjournals.org/content/license.

248 Diabetes Volume 68, February 2019

PERSPECTIVES

INDIA

BETES

postulated mechanisms that may underlie clinical effectsof SGLT2 inhibition and provides guidance for use of theseantihyperglycemic agents in patients with T2D and CKD.

THE ROLE OF THE KIDNEY IN GLUCOSEHOMEOSTASIS: SODIUM–GLUCOSECOTRANSPORTERS

Under normoglycemic to mildly hyperglycemic conditions,the kidney reabsorbs almost all glucose in the glomerularfiltrate (19). Glucose reabsorption occurs against its con-centration gradient and is driven by sodium symportersexpressed in the proximal tubule (20). Of these, SGLT2 andsodium–glucose cotransporter 1 (SGLT1) are the principalknown contributors. The complementary glucose transportkinetics of these two transporters permit almost completeresorption of filtered glucose (21). Experimental data in-dicate that SGLT2 is expressed on the luminal surface of theepithelial cells of the proximal convoluted tubule and isa low-capacity, high-affinity glucose transporter (Km ;1–4 mmol/L for glucose) with 1:1 Na+/glucose stoichiometry.As such, SGLT2 is responsible for the reabsorption of;90%

of filtered glucose (Fig. 1). SGLT1 is expressed on theluminal surface of the epithelial cells of the late proximaltubule and reabsorbs most of the remaining ;10% offiltered glucose (21–23).

In humans, glycosuria occurs when blood glucosereaches a threshold of about 180 mg/dL (10 mmol/L). How-ever, this threshold can range approximately 100–240 mg/dL (5.5–13 mmol/L) (24–27). Diabetes increasesthe glycosuric threshold to 200–240 mg/dL (11–13 mmol/L)and, in this way, exacerbates hyperglycemia. The exactmechanism behind this response is unclear but most likelyincludes increased expression of SGLTs. In studies ofmouse and rat models of T2D, SGLT1 and SGLT2 expres-sion are increased in the diabetic kidney (28–30). Corre-spondingly, tubular epithelial cells freshly isolated fromthe urine of humans with T2D exhibit increased expressionof SGLT2, and kidney tissue from patients with T2Ddisplays higher expression of SGLT1 protein and mRNA(31, 32). In sum, higher glucose reabsorptive capacity ofthe diabetic kidney likely results from increased expressionof SGLTs (33) (Fig. 1).

Figure 1—A and B: Glucose reabsorption via SGLT1 and SGLT2 in normal and diabetic kidney. Expressed apically in the epithelium of theproximal convoluted tubule, SGLT2 reabsorbs about 90% of glucose from the urinary filtrate. The remaining 10% is reabsorbed by SGLT1,a high-affinity and low-capacity transporter expressed apically in the epithelium of the straight descending proximal tubule.

diabetes.diabetesjournals.org Alicic and Associates 249

SGLT2 INHIBITION AND DKD

The BI 10773 (Empagliflozin) Cardiovascular Out-come Event Trial in Type 2 Diabetes Mellitus Patients(EMPA-REG OUTCOME) trial and the Canagliflozin Car-diovascular Assessment Study (CANVAS) Program werethe original large studies that demonstrated improve-ments in both CVD and CKD outcomes in over 17,000participants with T2D at high CVD risk (34–38). EMPA-REG OUTCOME enrolled approximately 7,000 partici-pants and followed them for a mean duration of 3.1 years.Study participants were randomized to empagliflozin (10 mgor 25 mg) or placebo. The empagliflozin group experiencedsignificantly lower rates of hospitalization for heart failure(35% relative risk reduction), death from CVD (38%relative risk reduction), and death from any cause (32%relative risk reduction) compared with the placebo group(34). Importantly, these observed risk reductions weremaintained across estimated glomerular filtration rate(eGFR) and albuminuria categories in more than 2,000participants with eGFR ,60 mL/min/1.73 m2 and/ormacroalbuminuria (35).

EMPA-REG OUTCOME also examined secondary kid-ney disease outcomes of incident or worsening nephrop-athy: new-onset albuminuria or progression to urinealbumin-to-creatinine ratio (UACR) .300 mg/g (macro-albuminuria), doubling of serum creatinine, initiation ofKRT, and death from kidney disease as a composite out-come and individual outcomes (36). The relative risk ofdeveloping incident or worsening nephropathy was 39%lower in the empagliflozin group compared with placebo(13% vs. 19%, P , 0.001) (36). A comparable relativerisk reduction for nephropathy was observed in partic-ipants with CVD who underwent coronary artery bypassgraft surgery (37). Notably, most participants in EMPA-REG OUTCOME also received treatment with ACE inhibitorsor angiotensin receptor blockers, agents that have beenshown to reduce DKD progression and prevent ESKD.

The CANVAS Program integrated data from two CVDoutcome trials enrolling over 10,000 participants withT2D, randomized to either canagliflozin or placebo andfollowed for a mean duration of 3.6 years (38). Theprimary composite outcome of death from CVD causes,nonfatal myocardial infarction, and nonfatal stroke oc-curred at a significantly lower rate in the canagliflozingroup compared with placebo (14% relative risk reduction,P , 0.001). The risk of progression to albuminuria wasdecreased by 27%, and the composite kidney disease out-come (40% eGFR decline, KRT, or death from kidneycauses) occurred 40% less frequently in the canagliflozingroup relative to placebo (38). The secondary analysis ofthe CANVAS Program showed that cardiovascular andkidney outcomes were consistent across the differentlevels of kidney function (eGFR 30–45, 45–60, 60–90,and $90 mL/min/1.73 m2); however, canagliflozintreatment had greater benefits on fatal/nonfatalstrokes in groups with eGFR ,60 mL/min/1.73 m2

(hazard ratio compared with placebo was 0.56 in the45–60 mL/min/1.73 m2 group and 0.32 in the 30–45 mL/min/1.73 m2 group) (39). Ongoing cardiovas-cular outcomes trials with two other SGLT2 inhibitors,dapagliflozin and ertugliflozin, will also report majorCKD outcomes (40).

Although the findings from the EMPA-REG OUTCOMEand CANVAS trials provide a strong signal that SGLT2inhibition preserves kidney function and improves overalland kidney survival in T2D, results from two clinical trialsprimarily designed to evaluate CKD outcomes with SGLT2inhibition are keenly awaited. The Canagliflozin and RenalEndpoints in Diabetes with Established NephropathyClinical Evaluation (CREDENCE) (ClinicalTrials.org iden-tifier NCT02065791) and A Study to Evaluate the Effectof Dapagliflozin on Renal Outcomes and CardiovascularMortality in Patients With CKD (Dapa-CKD) (Clinical-Trials.org identifier NCT03036150) trials are evaluatingeffects of canagliflozin or dapagliflozin on compositeprimary outcomes including ESKD, doubling of serumcreatinine (CREDENCE), $50% sustained decline ineGFR (Dapa-CKD), and kidney disease or CVD death inparticipants with established DKD (41). CREDENCE con-cluded early due to positive efficacy findings, and resultsare expected to be publicly released in early 2019 (42).Dapa-CKD is expected to report in 2021 (Table 1).

Preservation of eGFR and albuminuria reduction areclass effects of SGLT2 inhibitors. An initial effect observedwithin the first few weeks of SGLT2 inhibition is thereduction of eGFR by approximately 5 mL/min/1.73 m2,followed by stabilization over time (36,43–49). This phe-nomenon has been observed in patients with eGFR as lowas 30 mL/min/1.73 m2 (50). Compared with glimepiride,canagliflozin resulted in slower mean eGFR decline(0.5 mL/min/1.73 m2 per year for canagliflozin 100 mgdaily, 0.9 mL/min/1.73 m2 per year for canagliflozin300 mg daily, and 3.3 mL/min/1.73 m2 per year withglimepiride, P , 0.01 for between-group comparisons),despite achieving a similar level of glycemic control (46).Albuminuria reduction is also observed across levels ofalbuminuria and eGFR. Although it did not have a signif-icant effect on development of new-onset albuminuria inEMPA-REG OUTCOME, empagliflozin produced a 38%relative risk reduction in progression to severely increasedalbuminuria (11% vs. 16%, P , 0.001) compared withplacebo (36). Similarly, in the CANVAS Program, canagli-flozin produced a 27% reduction in progression to se-verely increased albuminuria and 1.7-fold higher rate ofalbuminuria regression (38). Among patients with base-line UACR .100 mg/g, treatment with dapagliflozindecreased 24-h urine albumin excretion by 36% (P ,0.001), and among those with eGFR 30–60 mL/min/1.73 m2, it decreased frequency of severelyincreased albuminuria (UACR .1,800 mg/g) comparedwith placebo (44, 51). Among patients with eGFR $30 to,50 mL/min/1.73 m2, treatment with canagliflozin wasassociated with greater decrease in UACR compared with

250 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019

Tab

le1—Sum

mary

ofclinicaltrials

evaluatingkid

neyoutco

mes

with

SGLT

2inhib

ition

Stud

yIntervention

Inclusioncriteria

Main

kidney

outcomes

EMPA-R

EG

OUTC

OME

(NCT01131676)

(34,36)

Empagliflozin

vs.placeb

ocT2D

cHigh

CVD

riskceG

FR.30

mL/m

in/1.73m

2

c39%

relativerisk

reduction

forincid

entor

worsening

nephrop

athy(12.7%

vs.18.8%

)c38%

relativerisk

reduction

forprogression

toalb

uminuria

(11.2%vs.16.2%

)c44%

relativerisk

reduction

ofdoub

lingofserum

creatinine(1.5%

vs.2.6%)

c55%

relativerisk

reduction

ofneed

forinitiation

ofKRT(0.3%

vs.0.6%

)

CANVASProgram

(NCT01032629,

NCT01989754)

(38)

Canagliflozinvs.

placeb

ocT2D

cHigh

CVD

riskcMean

eGFR

of76.5

mL/m

in/1.73m

2

cDecreased

progression

ofalbum

inuria(hazard

ratio0.73;95%

CI0.67

–0.79)cDecrease

incom

posite

outcomeof

asustained

40%red

uctionin

eGFR

,KRT,

ordeath

fromkid

neycauses

(hazardratio

0.60;95%

CI0.47

–0.77)

DECLA

RE-TIM

I58

(NCT01730534)

(40)

Dap

agliflozinvs.

placeb

ocT2D

cHigh

CVD

riskceG

FR$60

mL/m

in/1.73m

2

Results

pend

ing:cKidney

composite

endpoint

(sustained$40%

decrease

ineG

FRto

eGFR

,60

mL/m

in/1.73m

2and

/orESKD

and/or

renalorCVD

death)

VERTIS

CV

(NCT01986881)

(90)Ertugliflozinvs.

placeb

ocT2D

cHistory

ofatherosclerosis

ofthe

coronary,cereb

ral,or

perip

heralvascularsystem

s

Results

pend

ing:cKidney

composite

endpoint

(kidney

death,

KRT,

ordoub

lingof

serumcreatinine)

CREDENCE

(NCT02065791)

(41)Canagliflozinvs.

placeb

ocT2D

ceG

FR$30

to,90

mL/m

in/1.73m

2

cUACR.300

to#5,000

mg/g

cStab

ilizationon

maxim

umlab

eledor

tolerateddose

ofan

ACEinhib

itoror

angiotensinIIrecep

torblocker

Results

pend

ing:cKidney

composite

endpoint

(ESKD,doub

lingof

serumcreatinine,

andkid

neyor

CVD

death)

cChange

ineG

FRover

time

cChange

inalb

uminuria

overtim

e

Dap

a-CKD

(NCT03036150)

(87)Dap

agliflozinvs.

placeb

ocT2D

with

DKD

andnond

iabetic

kidney

disease

ceG

FR$25

to#75

mL/m

in/1.73m

2

cUACR$200

to#5,000

mg/g

cStab

ilizationon

maxim

umlab

eledor

tolerateddose

ofan

ACEinhib

itoror

angiotensinIIrecep

torblocker

(unlesscontraind

icated)

Results

pend

ing:cKidney

composite

endpoint

($50%

sustaineddecline

ineG

FR,E

SKD,or

kidney

orCVD

death)

cChange

ineG

FRover

time

cChange

inalb

uminuria

overtim

e

EMPA-K

IDNEY

(NCT03594110)

(91)

Empagliflozin

vs.placeb

oceG

FR$20

to,45

mL/m

in/1.73m

2

OReG

FR$45

to,90

mL/m

in/1.73m

2with

UACR

$200

mg/g

cClinically

approp

riatedose

ofan

ACEinhib

itoror

angiotensinIIrecep

torblocker

unlessnot

toleratedor

indicated

Results

pend

ing:cCom

posite

outcomeof

timeto

firstoccurrence

of:cKidney

disease

progression

(ESKD,sustained

decline

ineG

FRto

,10

mL/m

in/1.73m

2,kid

neydeath,

ora

sustaineddecline

of$40%

ineG

FRfrom

random

ization),OR

cCard

iovasculardeath

DECLA

RE-TIM

I58,

Dap

agliflozinEffect

onCard

iovascularEvents

trial.

diabetes.diabetesjournals.org Alicic and Associates 251

placebo (median percent reduction 230%, 221%, and28% in canagliflozin 100 mg daily, 300 mg daily,and placebo groups, respectively) (48). When comparedwith glimepiride treatment with canagliflozin 100 mg or300 mg daily in patients with at least moderately increasedalbuminuria (UACR $ 30 mg/g), decreased UACR by 32%(P = 0.01) and 50% (P , 0.001), respectively, despitesimilar glycemic control (46).

DIRECT EFFECTS OF SGLT2 INHIBITION ON THEDIABETIC KIDNEY

Knowledge of the biological mechanisms behind thekidney-protective effects of SGLT2 inhibition is evolving.

Although blood glucose lowering is central to DKD pre-vention, there are also likely direct effects independent ofglycemia.

One putative mechanism is normalization of glomerularhemodynamics through restoration of tubuloglomerularfeedback. Hyperfiltration with resulting hypertension inthe glomerular capillary circulation is an early hemody-namic change observed in at least 75% of patients withT1D and 40% of those with T2D (Fig. 1) (52,53). Glomer-ular hyperfiltration is driven by metabolic derangementsincluding hyperglycemia and hyperaminoacidemia, as wellas increased proximal tubular reabsorption of glucose andsodium chloride via SGLT1 and SGLT2 (Fig. 2).

Figure 2—Effects of diabetes and SGLT2 inhibition on nephron hemodynamics. A: Increased reabsorption of glucose by SGLT2 in theproximal convoluted tubule decreases delivery of solutes to the macula densa. The resulting decrease in ATP release from the basolateralmembrane of tubular epithelial cells reduces production of adenosine and produces a vasodilatation of the afferent arteriole. B: SGLT2inhibitors restore solute delivery to the macula densa with resulting adenosine activation and reversal of vasodilation of the afferent arteriole.

252 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019

Tubuloglomerular feedback is an adaptive mechanismthrough which reabsorption of sodium and chloride in themacula densa promotes adenosine release (Fig. 2). Aden-osine, in turn, acts in paracrine manner to constrict theafferent arteriole. In diabetes, as a result of increasedreabsorption of sodium and chloride in the proximaltubule, delivery to the macula densa is decreased, leadingto lower solute reabsorption and a consequent decrease inadenosine production. By promoting relative afferent ar-teriolar vasodilation, this mechanism contributes to glo-merular hyperperfusion, hypertension, and hyperfiltrationin diabetes (54).

By blocking reabsorption of sodium chloride in theproximal tubule, SGLT2 inhibition restores solute deliveryto the macula densa and thereby restores normal tubulo-glomerular feedback (Fig. 2). A net effect is reversal ofafferent vasodilation and normalization of glomerularhemodynamics (55). This effect has been observed withthe nonspecific SGLT2 inhibitor phlorizin in a T1D modelin rats and, more recently, with the selective SGLT2inhibitor empagliflozin in a mouse T1D model (56,57).In humans with T1D and glomerular hyperfiltration,treatment with empagliflozin decreased directly measuredGFR (inulin clearance) by 33 mL/min/1.73 m2 (mean6 SD1726 23 mL/min/1.73 m2 to 1396 25 mL/min/1.73 m2)in conjunction with decreased plasma flow to the kidney,lower plasma nitric oxide levels, and increased kidneyvascular resistance. This effect was only observed inpatients with diabetes with glomerular hyperfiltration(58).

SGLT2 inhibition may have additional anti-inflamma-tory and antifibrotic actions that protect the kidney. Inprimary proximal tubular cells, SGLT2 inhibition sup-pressed the generation of a hyperglycemia-mediated in-crease in reactive oxygen species (47,59). Experimental ratand mouse models of diabetes have shown attenuationof glomerulosclerosis and tubulointerstitial fibrosis withSGLT2 inhibition (60–62). Decreased urinary excretionof markers of kidney tubular injury (e.g., kidney injurymolecule 1) and inflammatory markers (e.g., interleukin-6)have been observed in humans with T2D treated withdapagliflozin (47).

EFFECTS OF SGLT2 INHIBITION ONRISK FACTORSFOR DKD

Glycemic control is known to decrease risk of DKD onset,particularly if implemented early in the course of diabetes(14,15). In patients with diabetes and preserved kidneyfunction, SGLT2 inhibition reduces HbA1c by approxi-mately 1% (63). Due to the intrinsic mechanism of action,the glycemic-lowering effects of SGLT2 inhibitors are bluntedin patients with low eGFR (36,39,43,44,48,63,64). For in-stance, the adjusted mean treatment difference in HbA1cwas 20.7% (P , 0.001) in patients with eGFR .60and #90 mL/min/1.73 m2 who received empagliflozinwhen compared with placebo, and in those witheGFR .30 and #60 mL/min/1.73 m2, the adjusted

mean difference was 20.4% (P , 0.001) (43). Pooledanalysis of phase III empagliflozin clinical trials con-firmed this finding with evidence of placebo-correctedreductions in HbA1c decreasing with declining eGFR(64). Treatment with dapagliflozin reduced HbA1c be-tween 0.3% and 0.4% in patients with eGFR .45and #60 mL/min/1.73 m2. No HbA1c reduction wasobserved in patients with eGFR #40 mL/min/1.73 m2

(44). As such, the antihyperglycemic effects of SGLT2inhibition seem less likely to confer kidney protectionin the setting of moderate-to-severe CKD.

As body fat loss per se may decrease albuminuria andglomerular hyperfiltration, weight reduction effect ofSGLT2 inhibition may indirectly protect the diabetic kid-ney (44,55). In patients with normal kidney function,SGLT2 inhibition leads to a loss of 60–80 g of glucose(240–320 calories) per day via glycosuria, with expectedweight loss of 2–3 lb (0.9–1.4 kg) per month (65). How-ever, weight loss plateaus after about 6 months of treat-ment, after achieving a total weight loss of 5–7 lb (2.3–3.2 kg) (63). After more than 2 years of dapagliflozintreatment in patients with T2D and a mean weight of225 lb (102 kg), experienced weight loss was 11 lb(5 kg) with a concomitant decrease in waist circumference(66,67). Notably, a recent pooled analysis of phase IIIempagliflozin trials and secondary analysis of the CANVASProgram found that the weight loss effects were main-tained in patients with eGFR as low as 30 mL/min/1.73 m2

(39, 64).Antihypertensive effects are observed with empagliflo-

zin, dapagliflozin, and canagliflozin. Each of them lowersystolic blood pressure by approximately 5 mmHg anddiastolic blood pressure by approximately 2 mmHg(63,68–70). The systolic blood pressure reduction appearsgreatest within 3–4 months of initiation of treatment withempagliflozin and dapagliflozin (34,66). In contrast toblood glucose lowering, the magnitude of blood pressurereduction is maintained, or perhaps increased, in patientswith low eGFR (39). For example, in patients with T2D, themean placebo-corrected changes in systolic blood pressureamong those treated with empagliflozin were 23 mmHgwith eGFR $90 mL/min/1.73 m2, 24 mmHg with eGFR60–89 mL/min/1.73 m2, 26 mmHg with eGFR 30–59mL/min/1.73 m2, and 27 mmHg with eGFR ,30mL/min/1.73 m2 (64). The mechanisms underlying bloodpressure reduction are likely multiple and may includenatriuresis, weight loss, and improved endothelial functionand vascular compliance (71–76).

The natriuretic effect may be enhanced in diabetes dueto greater proximal tubular sodium reabsorption related toincreased expression of SGLT2 and SGLT1 (77, 78). An-other postulated mechanism for the natriuretic effect ofSGLT2 inhibition is “cross talk” with other solute trans-porters, including the Na+/H+ exchanger 3 (NHE3). NHE3is responsible for much of the sodium reabsorption fromthe glomerular filtrate (79). In rats, SGLT2 and NHE3colocalize in the membrane of proximal tubular cells (80).

diabetes.diabetesjournals.org Alicic and Associates 253

SGLT2 inhibition with phlorizin inhibits sodium bicar-bonate reabsorption by NHE3, though the specificmechanism of this effect remains unclear (81).

CLINICAL USE OF SGLT2 INHIBITORS

Since the U.S. Food and Drug Administration (FDA) ap-proval of canagliflozin for the treatment of T2D in 2013,the SGLT2 inhibitor class has quickly gained usage. Ma-jor guidelines and consensus statements, such as theAmerican Diabetes Association (ADA) Standards of MedicalCare in Diabetes and the American Association of ClinicalEndocrinologists (AACE)/American College of Endocrinol-ogy (ACE) algorithm for the comprehensive managementof people with T2D, recommend SGLT2 inhibition becauseof the combined effects on glycemia, weight, and bloodpressure in people with preserved eGFR (82–84). Basedlargely on results of the EMPA-REG OUTCOME andCANVAS clinical trials, the consensus report from theADA and European Association for the study of Diabetes(EASD) recommends use of SGLT2 inhibitors as an add-onantihyperglycemic therapy of choice in patients who haveCVD or CKD (84). Dosing recommendations (eGFR.30 mL/min/1.73 m2 for dapagliflozin, canagliflozin,and ertugliflozin and .45 mL/min/1.73 m2 for empagli-flozin), which are based on the limited antihyperglycemicefficacy of SGLT2 inhibition in patients with lower eGFR,are not changed.

Though both empagliflozin and canagliflozin have nowbeen approved by the FDA for the indication of reducingthe risk of cardiovascular events and cardiovascular deathin adults with T2D and established CVD, to date, SGLT2inhibitors have not been recommended for the expresspurpose of improving CKD outcomes (85,86). The currentrecommendations to limit use of SGLT2 inhibitors byeGFR criteria may change once results of CREDENCEand other ongoing clinical trials with primary CKD out-comes are reported (Table 2) (41,42,87).

CONCLUSIONS

SGLT2 inhibitors show great promise for preventionand treatment of DKD. Trials with empagliflozin havedemonstrated, for the first time, a reduction in all-causeand cardiovascular mortality in patients with T2D andCKD. The mortality risk in this population has hereto-fore been unacceptably high and largely unmitigated;thus, the importance of improving survival while main-taining kidney function in patients with DKD is of urgentand utmost importance. Research is needed to informthe use of SGLT2 inhibitors in the setting of T1D andperhaps for indications outside of diabetes, such as CKDwithout diabetes. Progress on these fronts is alreadyunder way. For example, the dual SGLT1/2 inhibitorsotagliflozin is currently under study for use in patientswith T1D (88,89). Empagliflozin will soon be studied

Table 2—Summary of dosing recommendations for FDA-approved SGLT2 inhibitors

Agent Usual dosing recommendations Renal dosing recommendations

Canagliflozin c The recommended starting dose is 100 mg oncedaily, taken before the first meal of the day.

c The dose can be increased to 300mg once daily inthose who require additional glycemic control.

c Assess kidney function before initiating and periodicallythereafter.

c Limit the dose to 100 mg once daily in patients who havean eGFR of 45 to ,60 mL/min/1.73 m2.

c Initiation is not recommended in patients with aneGFR ,45 mL/min/1.73 m2.

c Use is not recommended when eGFR is persistently,45 mL/min/1.73 m2.

c Use is contraindicated in patients with an eGFR,30 mL/min/1.73 m2.

Dapagliflozin c The recommended starting dose is 5 mg oncedaily, taken in the morning, with or without food.

c The dose can be increasedto 10 mg once daily in those tolerating themedication who require additional glycemiccontrol.

c Assess kidney function before initiating and periodicallythereafter.

c Initiation is not recommended in patients with an eGFR,60 mL/min/1.73 m2.

c Use is not recommended in patients with an eGFRpersistently between 30 and ,60 mL/min/1.73 m2.

cUse is contraindicatedwith an eGFR,30mL/min/1.73m2.

Empagliflozin c The recommended starting dose is 10 mg oncedaily, taken in the morning, with or without food.

c The dose can be increased to 25 mg once daily.

c Assess kidney function before initiating.c Initiation is not recommended if eGFR is,45 mL/min/1.73 m2.

c Discontinue if eGFR is persistently,45 mL/min/1.73 m2.

Ertugliflozin c The recommended starting dose is 5 mg oncedaily, taken in the morning, withor without food.

c The dose can be increased to 15 mg once daily inthose tolerating the medication who needadditional glycemic control.

c Assess kidney function before initiating and periodicallythereafter.

c Initiation is not recommended in patients with an eGFR of30 to ,60 mL/min/1.73 m2.

c Continued use is not recommended in patients with aneGFR persistently between 30 and,60mL/min/1.73 m2.

c Use is contraindicated with eGFR ,30 mL/min/1.73 m2.

254 SGLT2 Inhibition and Diabetic Kidney Disease Diabetes Volume 68, February 2019

for primary CKD outcomes and cardiovascular deathsamong those with established diabetic and nondiabeticCKD. Elucidation of the biological mechanisms underlyingthe effects of SGLT2 inhibition is necessary to advanceunderstanding and more fully optimize clinical applica-tions of these agents for the treatment of diabetes, CKD,and CVD.

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