Review
Effects
of
glucose-lowering
agents
on
surrogate
endpoints
and
hard
clinical
renal
outcomes
in
patients
with
type
2
diabetes
A.J.
Scheen
a,b,*
aDivisionofClinicalPharmacology,CentreforInterdisciplinaryResearchonMedicines(CIRM),UniversityofLie`ge,Lie`ge,Belgium bDivisionofDiabetes,NutritionandMetabolicDisorders,DepartmentofMedicine,CHUdeLie`ge,Lie`ge,Belgium
Introduction
Inparallelwiththetype2diabetesmellitus(T2DM)worldwide pandemic,diabetickidneydisease(DKD),whichisalsoassociated with cardiovascular (CV) morbidity and mortality, has now become the leading cause of end-stage renal disease (ESRD) [1]. Renal impairment in T2DM results in high healthcare utilizationand costs[2].Thus,both thepreventionofDKDand
itsappropriateearlymanagementtoretardprogressiontoESRD representmajorchallengesinpatientswithT2DM[3–5].
Inadditiontoinhibitionoftherenin–angiotensin–aldosterone system (RAAS), tight glucose control is also an established modality for preventing the development and progression of albuminuria[6].Evidence suggests it can ameliorateestimated glomerularfiltrationrate(eGFR)declines,althoughthesebenefits appear tobemostpronouncedwhen appliedtoT2DMpatients withearlystagesofDKDandlongerfollow-updurations[7,8].Most antihyperglycaemic medications can be safely used in patients withmild-to-moderateDKD.However, severalglucose-lowering agents are either not advisable or require dose adjustments in cases of more advanced stages of renal disease [6–10]. Of note, metformin, the first-line treatment for pharmacological
ARTICLE INFO Articlehistory:
Received16August2018
Receivedinrevisedform17September2018 Accepted8October2018
Availableonlinexxx Keywords:
Chronickidneydisease DPP-4inhibitor GLP-1receptoragonist Metformin SGLT2inhibitor Thiazolidinedione Type2diabetes ABSTRACT
Diabetickidneydisease(DKD)representsanenormousburdeninpatientswithtype2diabetesmellitus
(T2DM).Preclinicalstudiesusingmostglucose-loweringagentshavesuggestedrenal-protectiveeffects,
buttheproposedmechanismsofrenoprotectionhaveyettobedefined,andthepromisingresultsfrom
experimentalstudiesremaintobetranslatedintohumanclinicalfindingstoimprovetheprognosisof
patientsatriskofDKD.Also,itis importanttodistinguisheffectsonsurrogateendpoints,suchas
decreasesinalbuminuriaandestimatedglomerularfiltrationrate(eGFR),andhardclinicalendpoints,
suchasprogressiontoend-stagerenaldisease(ESRD)anddeathfromrenalcauses. Dataregarding
insulintherapyaresurprisinglyscarce,anditisnearlyimpossibletoseparatetheeffectsofbetterglucose
control from those of insulin per se, whereas favourable preclinical data with metformin,
thiazolidinedionesanddipeptidylpeptidase(DPP)-4inhibitorsareplentiful,andpositiveeffectshave
beenobservedinclinicalstudies,atleastforsurrogateendpoints.Themostfavourablerenalresultshave
been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose
cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR
declinehavebeenreportedwiththeseclassesofglucose-loweringmedicationscomparedwithplacebo
andotherglucose-loweringagents.Moreover,inlargeprospectivecardiovascularoutcometrialsusing
compositerenaloutcomesassecondaryendpoints,bothGLP-1RAsandSGLT2isaddedtostandardcare
reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine,
progressiontoESRDandkidney-relateddeath;however,todate,onlySGLT2ishavebeenclearlyshown
toreducesuchhardclinicaloutcomes.Yet,astherenoprotectiveeffectsofSGLT2isandGLP-1RAsappear
tobeindependentofglucose-loweringactivity,theunderlyingmechanismsarestillamatterofdebate.
Forthisreason,furtherstudieswithrenaloutcomesasprimaryendpointsarenowawaitedinT2DM
patientsathighriskofDKD,includingtrialsevaluatingthepotentialadd-onbenefitsofcombined
GLP-1RA–SGLT2itherapies.
C 2018ElsevierMassonSAS.Allrightsreserved.
* Correspondingauthorat:DepartmentofMedicine,CHUdeSartTilman(B35), 4000Lie`ge1,Belgium.
E-mailaddress:andre.scheen@chuliege.be.
Available
online
at
ScienceDirect
www.sciencedirect.com
https://doi.org/10.1016/j.diabet.2018.10.003
managementofT2DM,maynowbeusedinpatientswithstable, moderaterenaldysfunction,accordingtorecentguidelines[11].
Intensive glucose control with the classic glucose-lowering agents,includinginsulin,reducestheriskof(micro)albuminuria, althoughevidenceislackingthat itcanreducetheriskof hard clinicalrenaloutcomeslikedoublingofserumcreatininelevels, ESRDanddeathduetorenaldisease,presumablybecauseof too-shortfollow-upsinmostoftheavailabletrials[12].However,as add-ons to standard care, new glucose-lowering agents have demonstratedrenoprotectiveeffectsbeyondjustimprovementof glucose control [13–16]. In particular, glucagon-like peptide-1 receptoragonists(GLP-1RAs)[17]and,evenmoreimpressively, sodium–glucosecotransportertype-2inhibitors(SGLT2is)[18–21] have shown positive effects on composite renal outcomes, including hard clinical endpoints, in T2DM patients with establishedCVdisease.
The aim of the present narrative review is to analyze and comparetheeffectsofold andnewglucose-loweringagents on surrogaterenalendpointsandclinicalrenaloutcomesinpatients
withT2DM(Table1).Theunderlyingmechanismsresponsiblefor
nephroprotectionweremainlyinvestigatedinin-vitroandin-vivo experimentsusinganimalmodels,andareherebrieflydiscussed foreachpharmacologicalclass.
Metformin
Metformin elicitsat least partof itstherapeutic activityvia activationoftheAMP-activatedkinase(AMPK)pathway.AMPKisa metabolicsensorthatregulatescellularenergybalance,transport, growth,inflammationandsurvivalfunctions;inthekidney,AMPK playsauniqueroleatthecrossroadsofenergymetabolism,ionand water transport,inflammation and stress [22]. Pharmacological activatorsofAMPKlikemetforminhaveshownrenal-protective effectsinnumerousexperimentalstudies[23].Renalcellsunder hyperglycaemicorproteinuricconditions exhibitinactivationof celldefencemechanisms(AMPKandautophagy)andactivationof pathologicalpathways[mammaliantargetofrapamycin(mTOR), epithelial-to-mesenchymal transition, endoplasmic reticulum stress,oxidativestress] [24].Activationof AMPKby metformin suppresses endoplasmic reticulum stress by angiotensin II, aldosteroneandhighglucoselevels,andalsoreducesrenalfibrosis related to transforming growth factor (TGF)-
b
[25]. In a concentration-dependentmanner, metforminhasalsoexhibited antiapoptoticeffectsonhumanpodocytesviaactivationofAMPK andinhibition ofmTORsignalling[26].Experimentalstudiesin miceconcludedthattheunderlyingmechanismsfortheprotective effects of metformin against renal fibrosis include AMPKa
2-dependent targeting of TGF-b
1 production and AMPKa
2-inde-pendenttargetingofTGF-b
1downstreamsignalling[27]. Otherdatahaveindicatedthatreduced phosphorylationofacetyl-CoA carboxylase(ACC)afterrenalinjury contributestothe develop-ment of tubulointerstitialfibrosis, and that phosphorylation of ACC,atargetforenergy-sensingAMPK,isrequiredforantifibrotic metforminactionsinthekidney[28].Thus,numerousin-vitroand in-vivo studies have revealed nephroprotective effects with metformin, and these effects have been demonstrated to be mediatedviatheAMPK–mTORsignallingaxis[29].
Metforminactivatesnot onlyAMPK,but alsoprotein deace-tylaseSIRT1.In fact,metforminhasbeenshowntopreventthe hyperglycaemia-inducedreductionofSIRT1proteinlevelswhile ameliorating glucose uptake into podocytes and decreasing glomerularfiltrationbarrierpermeability.Indeed,thepotentiating effect of metformin on high-glucose-induced insulin-resistant podocytesseemstobedependentonSIRT1activityinadditionto AMPK, thereby arguing in favour of pleiotropic effects with metforminaction[30].Recentexperimentaldatainaratmodelof chronic kidney disease (CKD) showed that kidneys from the metformingroupexhibitedsignificantlyless cellularinfiltration, fibrosisandinflammation,andthatmetforminprotectedagainst thedevelopmentofsevererenalfailure(whilepreservingcalcium phosphorus homoeostasis) and vascular calcification. Of note, thesepositiveeffectswereindependentofanyglucose-lowering effectin this model usingnon-diabeticrats[31].Overall, these preclinicaldatasuggestthatthepotentialbenefitsofmetforminon renaloutcomesinpatientswithT2DMmaywellextendbeyondits antihyperglycaemicactivity.
Nevertheless,suchpositivepreclinicalresultsarestillawaiting furtherclinicaltranslation[32].Indeed,humandataarestillrather scarce. In the United Kingdom Prospective Diabetes Study (UKPDS), the proportion of T2DM patients with urinary albu-min>50mg/L (the only surrogate marker used as a renal outcome in this landmark study) did not differ significantly betweenthemetformingroup(23%),theconventionaldiet-treated group(23%) andtheintensive (sulphonylureaor insulin)group (24%)overamedianfollow-upof10.7years[33].InADiabetes Outcome Progression Trial (ADOPT), a 5-year study comparing initialtherapywithmetforminvsglyburide(glibenclamide)and rosiglitazone in T2DM patients, the urinary albumin/creatinine ratio (UACR) rose slowly in the metformin group, whereas it initiallyfellwithrosiglitazoneandglyburideoverthefirst2years, thenroseslowlyovertime.Ontheotherhand,thelatedeclinein eGFR with metformin was more pronounced than with rosi-glitazone,butlessmarkedthanwithglyburide[34].
Mostclinicalstudieshavebeeninterestedinthesafetyissuesof metformininT2DMpatientswithrenalimpairmentasregardsrisk oflacticacidosisratherthantheimpactofmetforminonsurrogate or clinical renal outcomes(for reviews, see Crowley et al. and Inzucchietal.[35,36]).Nevertheless,basedontherelevantclinical
Table1
Effectsofglucose-loweringagentsonrenalsurrogateendpointsandclinicaloutcomesinpreclinicalanimalmodelsandclinicalstudiesinpatientswithtype2diabetes. Medications Preclinicalresults Clinicalresults
In-vitroandin-vivodata Reductionofalbuminuria SlowingofeGFRreduction LessprogressiontoESRD Metformin Positive Notproven Notproven Notproven
Sulphonylureas None Noa
Noa
Noa
Glinides None Nodata Nodata Nodata
Alpha-glucosidaseinhibitors Rare Nodata Nodata Nodata Thiazolidinediones Positive Yes Notproven Notproven DPP-4inhibitors Positive Yes Notproven Notproven GLP-1receptoragonists Positive Yes Yes Notproven
SGLT2inhibitors Positive Yes Yes Yes
Insulintherapy Rare Notprovenb
Notprovenb
Notprovenb
eGFR:estimatedglomerularfiltrationrate;ESRD:end-stagerenaldisease;DPP-4:dipeptidylpeptidase4;GLP-1:glucagon-likepeptide1;SGLT2:sodium–glucose cotransportertype2.
aLessfavourableresultscomparedwithmetformininobservationalstudies. bImpossibletodiscriminatefrompossibleeffectsduetobetterglucosecontrol.
observations,metforminappearstobea promisingdrugin the treatmentofprogressiverenaldamage[37].Severalobservational findingsdemonstrated betterrenal outcomesin T2DMpatients initiated or treated with metformin than in those initiated or treatedwithsulphonylureas(seebelow).However,becauseofthe possible biases inherent in observational studies, randomized controlledtrials(RCTs)aretheessentialnextsteptoconfirmthese findings.
Sulphonylureas
Incontrasttothehuge amountof experimentalanimaldata supportingtherenal-protectiveeffectsofmetformin[37],nosuch dataareavailableintheliteratureforsulphonylureas[38,39].
Intheabove-mentionedADOPTstudycomparinginitialtherapy withthesulphonylureaglyburidevs.metforminandrosiglitazone in newlydiagnosed T2DM patients,a late decline in eGFR was observedinallthreegroups,albeitmoremarkedwithglyburide than with either metformin or rosiglitazone over the 5-year follow-up [34]. The Action in Diabetes and Vascular disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) reported that intensive glucose control using modified-release (MR)gliclazidepreventedESRDinpatientswithT2DM[40]:aftera mediandurationof5years,intensiveglucosecontrolsignificantly reducedmicroalbuminuriaby9%,macroalbuminuriaby30%and riskofESRDby65%[hazardratio(HR):0.35,P=0.02],although there were very few such events (only 7 vs. 20 ESRD cases). However,this effecton ESRDwasconfirmedin thesubsequent ADVANCE-ONtrialafteramedianof5.4additionalyears(29vs. 53 events; HR: 0.54, P<0.01),and thebenefit wasgreater in patients withearlier-stage DKDand withwell-controlledblood pressure[41].Ofnote,theexperimentaldesignofthestudydidnot allowseparationoftheeffectsofsulphonylureapersefromthatof betterglucosecontrol.
Using electronic health records from two primary-care networks and compared with metformin as the reference, sulphonylurea exposure in newly diagnosed T2DM patients trended towards an association with an increased risk of developing proteinuria [adjustedhazard ratio (aHR): 1.27, 95% confidenceinterval(CI):0.93–1.74],butshowedaclearassociation withanincreasedriskofeGFRreductionto<60mL/min/1.73m2
(aHR:1.41,95%CI:1.05–1.91)[42].
Severalretrospective comparisonswereperformed usingthe USVeteransAffairsnationaldatabase.Inacohortof93,577T2DM patients who had filled an incident oral antidiabetic drug prescriptionandhadaneGFR60mL/min/1.73m2atinclusion, sulphonylurea users compared with metformin users had an increasedriskoftheprimaryoutcome(persistentdeclineof25% ineGFRfrombaselineoradiagnosisofESRD:aHR:1.22,95%CI: 1.03–1.44)[43].Theseresultswereconfirmedin13,238veteran T2DMpatientswhoinitiatedeithersulphonylureaormetformin treatment.Ahigherriskofkidneyfunctiondeclineordeathwas seen with sulphonylurea compared with metformin, and the difference appeared to be independent of changes in glycated haemoglobin(HbA1c),systolicbloodpressureandbodymassindex
(BMI)overtime[44].Of175,296patientswithnewlydiagnosed T2DMandDKD,initiationofasulphonylureavs.metforminwas associatedwithasubstantialincreaseinmortalityacrossallranges of eGFR evaluated (HR ranged from1.25 to 1.69). The biggest absoluteriskincrease wasobservedinthosewith moderate-to-severedecreasesineGFR(30–44mL/min/1.73m2)[45].
In a real-world cohort of T2DM patients with albuminuria (urinaryalbumincreatinineratio[UACR]>30mg/g)who initiat-edeithersulphonylureaorsitagliptinasadd-ondualtherapyto metformin(dataextractedfromthecomputerizedmedicalrecords
of a large managed-care organization in Israel), while both pharmacologicalapproachesreducedalbuminuria,sulphonylureas seemedtoprovidelessofareductioninalbuminuriaindependent ofglycaemiccontrolcomparedwiththeDPP-4inhibitor[46].
Another real-life study investigated the effects of two commonly prescribed sulphonylureas on kidney outcomes in 4486T2DMpatientstreatedwitheitherglimepirideorgliclazide for>2years and followed for a median duration of 4.7years [47]. In a matchedcohort using propensityscores with12,122 person-years of follow-up, there was no significant difference between thetwo sulphonylureasinriskof ESRDordoublingof creatinine,althoughtherewasatrendtowardshigherrisksinthe glimepiridegroupthaninthegliclazidegroup,reachingstatistical significanceinsomesubgroups[47].
Thus,sulphonylureasappeartoexertlessofanephroprotective effect,especiallycomparedwithmetformin,althoughresultsfrom observationalstudiesrequireconfirmationbyRCTs.Inaddition,no studyspecificallyinvestigatedtheeffectsofotherinsulin-secreting agents,suchasrepaglinideandnateglinide,onUACRoranyother renaloutcomes.
Alpha-glucosidaseinhibitors
In animal models, the alpha-glucosidase inhibitor acarbose suppressedbloodglucoselevelsinmildlyinsulin-deficientratsand reducedthenumberofanionicsitesintheglomerularbasement membrane,whichmighthelptopreventitsincreasedpermeability leading to albuminuria [48]. However, human data are scarce [49].InT2DMpatientsnotwellcontrolledbysulphonylureasand metformin, additional acarbose therapy for 6 months provided similar glycaemic control and changes in eGFR and UACR comparedwithpioglitazone[50].
IntherecentAcarboseCardiovascularEvaluation(ACE)trialto evaluatetheeffectsofacarboseonCVanddiabetesoutcomesin Chinesepatientswithcoronaryheartdiseaseandimpairedglucose tolerance, after a median follow-up of 4.4years, incidental impairedrenalfunction(definedaseGFR<30mL/min/1.73m2,
doublingofbaselineserumcreatinineorhalvingofbaselineeGFR) didnotdifferbetweentheacarbosegroupandtheplacebogroup (41/3272vs.50/3250,respectively; HR:0.81,95%CI:0.54–1.23; P=0.33)[51].
Glitazones
Ofalltheglucose-loweringagents,thiazolidinediones(TZDs) are those with thegreatest anti-inflammatory activity [52], an effectthatmaycontributetonephroprotection[53].TZDsmayalso interferewithmostofthepathogeneticpathwaysinvolvedinthe developmentandprogressionofDKD,astheyhavebeenshownto reducehyperglycaemiaandinsulinresistance,lowerarterialblood pressure, improve endothelial function, reduce inflammatory processes and oxidative stress, lower TGF-
b
and downregulatetheRAAS [54,55].Datafromseveral animal andhumanstudies
supportthenotionthatTZDsreduceUACRandmaypreventthe development of renal impairment [55]. In a meta-analysis of 15 RCTs (five with rosiglitazone and 10 with pioglitazone) involving2860T2DMpatients,treatmentwithTZDssignificantly decreasedUACRandproteinexcretion[56].However,inpatients withadvanceddiabeticnephropathy,noreductioninproteinuria wasobservedinpatientstreatedwithpioglitazonecomparedwith glipizide for 4months [57]. In a study that compared add-on pioglitazone with basal insulin, both treatments improved glycaemic control, but only pioglitazone was observed to beadvantageousby preservingrenalfunctionwhenused asan
add-ontherapyfor T2DMpatients inwhomsulphonylurea and metforminregimenshadfailed[58].
In a small study of TD2M patients with microalbuminuria, rosiglitazonecomparedwitheithernateglinideorplacebo signifi-cantly reduced albumin excretion and ameliorated glomerular hyperfiltrationatanearlystageofT2DMaswellasincipientDKD, while also improving nitric oxide bioavailability and renal endothelialdysfunction[59].InADOPT,initialmonotherapywith rosiglitazoneslowedtheriseofUACRcomparedwithmetformin, preserved eGFR compared with glyburide, and lowered blood pressurerelativetobothactivecomparatorsovera5-yearperiod [34]. In a post-hoc analysis from the Prospective Pioglitazone ClinicalTrialinMacrovascularEvents(PROactive),patientswhohad DKDandweretreatedwithpioglitazonecomparedwithplacebo werelesslikelytoreachthecompositeendpointofall-causedeath, myocardialinfarctionandstroke,independentlyoftheseverityof renalimpairment. However, there was an unexpectedly greater decline in eGFR with pioglitazone (between-group difference: 0.8mL/min/1.73m2/year) than with placebo [60]. Clinicalrenal
outcomeswerenotinvestigatedinthestudy.
Therefore,whethertheuseofTZDshasapositiveornegative impacton renal outcomesin T2DMpatients remains an open, unansweredquestion[61].In therecentlypublishedlarge-scale prospectiveInsulinResistanceInterventionafterStroke(IRIS)trial, whichdemonstratedsignificantriskreductionsofbothrecurrent strokeandmyocardialinfarctionwithpioglitazonecomparedwith placebo as add-ons to standard care, no renal endpoints were reportedon[62].Thus,therelativelackofevidencedemonstrating theeffectsofTZDsonhardrenaloutcomesmandatestheneedfor well-designedRCTsfocusedonthisparticularobjective[55].
DPP-4inhibitors
DPP-4isareincretin-basedtherapiesthatlowerbloodglucose levelswithoutinducinghypoglycaemiaorweightgainwhilehaving good CV safety profiles [63]. Theirglucose-lowering efficacy is maintainedinT2DMpatientsatallstagesofCKD,andtheyaresafe
touse [64–66].However,itis recommendedtoreducedosesof
alogliptin, saxagliptin, sitagliptin and vildagliptin according to reductionsineGFRtoguaranteeconsistentdrugexposurestothese medications,whichareexcretedviathekidneys[67,68].Incontrast, aslinagliptinhasbiliaryratherthanrenalexcretion,itsusualdose maybemaintainedwhateverthestateofrenalfunction[69].
SeveralrecentreviewshaveexploredtheeffectsofDPP-4ison surrogate renal outcomes [70–72]. Renal protection has been demonstrated in various animal models implicating different underlyingmechanismsindependentofglucosecontrol,including: upregulationof GLP-1 and GLP-1 receptors; inhibition of renal DPP-4activity;attenuationofinflammasomeactivation,reduction of oxidative stress; mitochondrial dysfunction and apoptosis; suppressionofconnective-tissuegrowthfactor;limitationof
TGF-b
-related fibrosis and nuclear factor (NF)-k
B p65-mediated macrophage infiltration; reduction of renal tubulointerstitial fibronectin; upregulation of stromal cell-derived factor-1; sup-pression of advanced glycation end-products; regulation of proliferation of preglomerular vascular smooth muscle and mesangialcells;and attenuationofrises inbloodpressure[70– 73].However,despitesuchpromisingresultsinanimal models, data on surrogate biological markers of renal function (UACR, eGFR)andclinicalrenaloutcomes(progressiontoESRD)arestill relativelyscantyinpatientswithT2DM,andmostlydemonstrate thesafety rather than true efficacy of DPP-4is regarding renal protection[70].In overweight patients with T2DM without DKD, 12-week treatment with sitagliptin had no measurable effect on renal
haemodynamics,andwasnotassociatedwithsustainedchangesin tubular function or alterations in markers of renal damage [74]. The Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) was mainly a CV outcome trialtodemonstratetheCVsafetyofsitaglitptin[75].Inapost-hoc analysisofTECOS,renaloutcomeswereevaluatedoveramedian periodof3 years,withparticipantscategorizedatbaseline into differenteGFRstages[76].Kidneyfunctiondeclinedatthesame rateinboth treatmentgroups, butwitha marginallyloweryet constanteGFR difference( 1.3mL/min/1.73m2)inthose
parti-cipants assigned to sitagliptin compared with those receiving placebo[76](Table2).
IntheSaxagliptinAssessmentofVascularOutcomesRecorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 study [77], there were no meaningful differences between the saxagliptin vs placebo treatment arms, respectively, in any of the prespecified renal safetyoutcomes:doublingofserumcreatinine(2.02%vs.1.82%); initiation of chronic dialysis, renal transplantation, or serum creatinine>6.0mg/dL (0.61%vs. 0.67%); and the composite of doublingofserumcreatinine,initiationofchronicdialysis,renal transplantationandserumcreatinine>6.0mg/dL(2.2%vs.2.0%)
[78](Table 2). Overall changes in eGFR during follow-up were
similarinthesaxagliptinandplaceboarms.However,asignificant reductioninUACRwasobservedwithsaxagliptincomparedwith placebo ( 34.3mg/g; P<0.004), driven mainly by decreased levelsinpatientswithmacroalbuminuriaatbaseline(-283mg/g; P=0.002),althoughchangesinUACRdidnotcorrelatewiththose inHbA1c[78].ThefrequencyofUACRprogressionwassignificantly
lower with saxagliptin compared with placebo in all patients exceptthosewithsevererenalimpairment.Otherrenalendpoints appeared at relatively balanced rates in patients treated with saxagliptin compared with placebo, irrespective of renal im-pairment [79]. Also, in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE), changesineGFRfrombaseline(whateverthebaselinelevel)and ratesofinitiationofdialysisweresimilarbetweenalogliptinand placebo[80](Table2).
Finally, pooled analyses of placebo-controlled RCTs with linagliptinrevealeda28%reductioninUACR(95%CI: 47to 2; P=0.0357)[81]and16%reductioninriskofcompositeDKDevents (HR: 0.84, 95% CI: 0.72–0.97; P=0.02) compared with placebo [82]. However, because of the limitations of such retrospective analysesofrathershort-termtrials,thepotentialoflinagliptinto improvekidneydiseaseoutcomesstillwarrantsfurther investiga-tion.Indeed,intheEfficacy,SafetyandModificationofAlbuminuria in Type2 DiabetesSubjectswith Renal DiseasewithLinagliptin (MARLINA-T2D),a dedicated phase-IIIplacebo-controlled RCTin patientswithinadequatelycontrolledT2DMandevidenceofDKD (UACRwith30–3000mg/gcreatininedespiteastablebackground of single RAAS blockade, and eGFR30mL/min/1.73m2),
lina-gliptinsignificantlyimprovedglycaemiccontrolwithnosignificant effectonUACRcomparedwithplaceboandnosignificantchangein placebo-adjusted eGFR [83]. Although there was no conclusive evidenceofrenoprotectiveeffectsinthe24-week MARLINA-T2D trial,previousresearchhadsuggestedthatclinicallyevidentrenal benefitsmightdevelopwithlonger-termtreatment[84].
Overall, the renal-protective potential of DPP-4is remains largely unproven in humans and merits further investigation
[70,72]. Several reasons may explain why DPP-4is failed to
positivelyimpactrenaloutcomesinRCTs.First,theyweredesigned todemonstratenon-inferiority,ratherthansuperiority,withCV outcomes as primary endpoints. Furthermore, adjustment of glucose-loweringtherapieswasallowed,whichresultedin only a small HbA1c difference between the active-treatment and
lastingonly1.5to3years.Thus,thereisanurgentneedfor long-termRCTsthatareadequatelypoweredandbasedonhardrenal outcomestoascertain(orcontradict)thetherapeuticbenefitsof DPP-4isinpatientswithT2DMandDKD.
Theplacebo-controlledCardiovascularandRenalMicrovascular Outcome Study with Linagliptin (CARMELINA) trial aimed to evaluatetheeffectsoflinagliptinonbothCVandkidneyoutcomes inastudypopulationofT2DMpatientsathighriskofCVand/or kidneyevents[85].Therecruitedpopulationinthisuniquestudy differedfromthoseofpreviousstudieswithDPP-4isinthat60% ofpatientshadsignsofrenaldysfunction(eithereGFR<60mL/ min/1.73m2oralbuminuria),incontrastto
<25%inothertrials. Whiletheprimaryoutcomewastheclassicthree-point combina-tion of major CV events, the key secondary outcome was a composite oftimetofirstsustainedappearanceofESRD,40% decrease in eGFR from baseline and kidney-related death. The resultswerepresentedatthe54thAnnualMeetingoftheEuropean AssociationfortheStudyofDiabetes(EASD;4October2018),but haveyettobepublished.Nosignificantdifferenceswereobserved betweenthelinagliptinandplacebogroupsforeitherCVorrenal compositeendpoints.Linagliptinwasassociatedwithasignificant reductioninalbuminuriawithnoeffectivechangeineGFR.
GLP-1receptoragonists
GLP-1RAsactonthetraditionalriskfactorsofprogressivekidney disease, including improvement of glucose control, lowering of bloodpressureandweightreduction.Moreover,GLP-1RAsmayalso havedirecteffectson thekidney,includingthe intrarenalRAAS, ischaemia/hypoxia,apoptosisandneuralsignalling(fora review, seeThomas[17]).However,themechanismsthatmayunderlieany directactionsinthekidneyhaveyettobeestablished[86].The GLP-1 receptor seems to be expressed in glomeruli and arterioles, whereas kidney-protective actions independent of the GLP-1 receptorhavebeenproposed.GLP-1inducesnatriuresisbyreducing sodium/hydrogenexchangerisoform3(NHE3)-dependentsodium reabsorptioninthe proximaltubule[17,87].GLP-1RAshavealso been shown to reduce inflammation, macrophage infiltration, oxidativestressandtype-IVcollagenaccumulationinthekidney
[17,88].Becausethebeneficialactionsofliraglutideareknowntobe
inhibitedbyaspecificadenylatecyclaseinhibitorandaselective protein kinase A (PKA) inhibitor, cAMP and PKA-dependent pathways downstream of GLP-1 receptor activation mayplay a criticalroleinrenalprotection[88].Inbothin-vivoandin-vitro studies, liraglutide prevented epithelial-to-mesenchymal transi-tion,which playsa significantrole in thedevelopment of renal fibrosis,byinhibitingactivationoftheTGF-
b
1/Smad3andERK1/2 signallingpathways,anddecreasingextracellularmatrixsecretion anddeposition[89].RenalGLP-1receptorshavebeenfoundtobe present in afferent arteriolar vascular smooth muscle cells, glomerular endothelial cells and macrophages, juxtaglomerular cells and proximal tubule, while GLP-1 has been reported to increase GFR,renal blood flow,and fractionalexcretion of both sodiumandpotassium[90].GLP-1RAsaresafetouseinT2DMpatientswithDKD[67]: 12-weektreatmentwithliraglutidehadnomeasurableeffectsonrenal haemodynamics,and led tono observable sustained changesin eithertubularfunctionormarkersofrenaldamage[74].Inanother study, short-term liraglutide treatmentalsodid not affect renal haemodynamics, but did decrease proximal tubular sodium reabsorption.Furthermore,areductioninangiotensinII concentra-tionwasobserved,whichmaycontributetorenalprotection[91]. IntheLiraglutideEffectandActioninDiabetes:Evaluationof CardiovascularOutcomeResults(LEADER)studyofCVoutcomes [92],theprespecifiedsecondaryrenaloutcomewasacompositeof
Table 2 Renal outcomes reported with dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients wit h type 2 diabetes and high cardiovascular risk. Studies DPP-4is vs comparator Active vs. placebo (n )
Median follow-up (years) Baseline mean eGFR Change in eGFR vs. placebo Baseline UACR (mg/g) Change in UACR (mg/g) vs. placebo
New-onset persistent macro
Doublin g o f serum creatinine Progression to ESRD requiring RRT
Composite renal outcome
Death from any cause a TECOS [75,76] Sitagliptin vs. placebo 7332 vs. 7339 3.0 74.9 1.34 ( 1.76 to 0.91), P < 0.0001 10.3 (3.5–34.6) 0.18 ( 0.35 to 0.02), P = 0.031 NA (micro: 7.8% vs. 7.9%) NA 1.4% vs. 1.5% NA 1.01 (0.90–1.14), P = 0.88 SAVOR–TIMI 53 [77,78] Saxagliptin vs. placebo 8280 vs. 8212 2.1 72.5 NA 203.6 (79.2– 848.4) 34.3 (NA), P < 0.004 2.2% vs 2.8% 1.1 (0.89– 1.36), NS 0.7% vs. 0.9%, 0.90 (0.61–1.3 2), NS b 1.08 c (0.88–1.32), P= 0.46 1.05 (0.74–1.50), P = 0.79 EXAMINE [80] Alogliptin vs. placebo 2701 vs. 2679 1.5 71.1 No difference d NA NA NA NA 0.9% vs. 0.8% NA 0.88 (0.71–1.09), P = 0.23 Results are expressed as hazard ratios (95% confidence interval). eGFR: estimated glomeru lar filtration rate; UACR: urinary albumin/creatinine ratio; macro/ micro: macroalb uminuria/microalbuminuria; ESRD: en d-stage renal disease; RRT: rena l replace ment therapy; NA: not available; NS: not significant. a Includes renal death, as those results are lacking in publications (presumably very few events). b includes serum creatinine > 6 mg/dL. c doubling of serum creatinine, dialysis, renal transplantation, serum creatinine > 6 mg/dL. d basal eGFR (mL/min/1.73 m 2): 90, 6.7 vs. 4.5; < 90 but 60, 0.6 vs. 1.0; < 60 but 30, 1.1 vs. 2.1; < 30, 0.2 vs. 1.6.
new-onsetpersistent macroalbuminuria, persistent doubling of serumcreatinine,ESRDanddeathfromrenaldisease[93].Aftera medianfollow-upof3.84yearsinT2DMpatientsathighriskofCV disease,thisrenaloutcomewasobservedinfewerparticipantsin theliraglutidethanintheplacebogroup(268/4668patientsvs. 337/4672,respectively; HR: 0.78, 95% CI: 0.67–0.92;P=0.003; TableIII).However,thisresultwasdrivenprimarilybythenew onset of persistent macroalbuminuria, whereas no significant differences were observed for persistent doubling of serum creatinine, ESRDand death due torenal disease(Table 3). The declineineGFRwasslightlylowerintheliraglutidethaninthe placebogroup(estimated36-monthtrialratio:1.02,95%CI:1.00– 1.03; P=0.01), corresponding to a 2% lower decrease with liraglutide: 7.44 vs. 7.82mL/min/1.73m2). Rates of renal
adverseevents(AEs)weresimilarinbothliraglutideandplacebo groups(15.1AEsand16.5AEsper1000patient-years, respective-ly),includingratesofacutekidneyinjury(7.1AEsand6.2AEsper 1000patient-years,respectively)[93].
In theTrial toEvaluateCardiovascularand OtherLong-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6), after a median follow-up of 2years, new or worsening nephropathy was less frequently reported in T2DM patientstreatedwithsemaglutidevs.placebo(HR:0.64, 95%CI: 0.46–0.88;P<0.01).Again,however,thiscompositeoutcomewas largely driven by a reduction in new-onset macroalbuminuria, whereasdoublingofserumcreatinineconcentrationsresultingin eGFRs45mL/min/1.73m2,ESRDand deathfromrenalcauses
were unaffected [94] (Table III). In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), a reduction in new-onset macroalbuminuria was reported in patients treated with once-weekly exenatide compared with placebo (2.2% vs 2.8%, respectively; P=0.03), with no significant changes in either microalbuminuria(7.2%vs.7.5%,respectively)orESRDrequiring renalreplacementtherapy(0.7%vs.0.9%)afteramedianfollow-up of3.2years[95](Table3).
In T2DMpatientswhohadhadrecentacutecoronaryevents fromtheEvaluationofLixisenatideinAcuteCoronarySyndrome (ELIXA),74.3% had normoalbuminuria, 19.2% had microalbumi-nuriaand6.5%hadmacroalbuminuria[96].After108weeks,the placebo-adjusted,least-squaresmeanpercentagechangesinUACR frombaselinewithlixisenatidewerenegligibleinpatients with normoalbuminuria,but reached 21.10%(95% CI: 42.25–0.04; P=0.0502)inpatientswithmicroalbuminuria,and 39.18%(95% CI: 68.53to 9.84;P=0.0070)inthosewithmacroalbuminuria. Lixisenatidewasalsoassociatedwithareducedriskofnew-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (HR: 0.808, 95% CI: 0.660–0.991; P=0.0404).
However,nosignificantdifferencesineGFRdeclinewereidentified betweentreatmentgroupsinanyUACRsubgroup.Inaddition,the proportion of patients with renal AEs was low and did not significantlydifferbetweentreatmentgroups[96].
Integrateddatafromninephase-II/-IIItrialsinT2DMpatients (n=6005)showedthatdulaglutidehadnoeffectoneGFR,butdid decreaseUACRslightlywithoutincreasingkidneyAEscompared witheither placebooractive comparators[97]. Inthe52-week AWARD-7 trialof patients with T2DMand moderate-to-severe DKD, once-weekly dulaglutide resulted in glycaemic control similar to that achieved with insulin glargine withno greater reductioninUACR,butwithsignificantlylessofadeclineineGFR (P=0.005for dulaglutide 1.5mg and P=0.009 for dulaglutide 0.75mgvs.insulin)[98].ThiswasconfirmedbyaUSstudyina real-lifesettingwhereinitiationofdulaglutidetherapy,compared withinsulinglargine,wasassociatedwithasignificantlysmaller decreaseineGFRovera1-yearperiod[99].Overall,these short-termdatasuggestthatdulaglutidehasthepotentialtoexertrenal protection in patients with T2DM, an effect that should be Table
3 Renal outcomes report ed for glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes and high cardiovascular risk. Studies GLP-1RA dose vs. comparator Active vs. placebo (n )
Median follow-up (years) Baseline mean eGFR Baseline UACR
Change
in
UACR
New-onset persistent macro
Doubling of serum creatinine Progression to ESRD requiring RRT
Composite renal outcome
Death from any cause a LEADER [92,93] Liragutide 1.8 mg once daily vs. placebo 4668 vs. 4672 3.84 80.4 Micro: 26.3%, macro: 10.5% 17% ( 12 to 21), P < 0.001 0.74 (0.60–0.91), P= 0.004 0.89 (0.67–1.19), P= 0.43 0.87 (0.61–1.24), P = 0.44 0.78 b (0.67–0.92), P= 0.003 0.85 (0.74–0.97), P= 0.02 SUSTAIN-6 [94] Semaglutide 0.5 or 1.0 mg once daily vs. placebo 1648 vs. 1649 2 N A N A N A 0.54 (0.37–0.77), P= 0.001 1.28 (0.64–2.58), P= 0.48 0.91 (0.40–2.07), P = 0.83 0.64 c (0.46–0.88), P= 0.005 1.05 (0.74–1.5 0), P = 0.79 EXSCEL [95] Exenatide ER 2 m g once weekly vs. placebo 7356 vs. 7396 3.2 76.6 NA NA 2.2% vs. 2.8% NA 0.7% vs. 0.9% NA 0.86 (0.77–0.98), P not tested Results are expressed as hazard ratios (95% confidence interval). eGFR: estimated glomerular filtration rate (mL/min/1.73 m 2); UACR: urinary albumin/creatinine ratio; ESRD: end -stage renal disease; RRT: renal replacement therapy; Micro: microalbuminuria; NA: not avail able; ER: extended release. a Includes renal death, as those results are lacking in public ations (presumably very few events). b Includes persistent doubling of serum creatinine, ESRD, death due to renal disease; another composit e endpoint was persistent doubling of serum cre atinine, need for continuous RRT (ESRD; HR: 0.85, 95% CI: 0.66–1.10 ,P = 0.20). c new or worsening nephropathy defin ed as new-onset persistent macroalbuminuria (macro), persistent doubling of serum creatinine, creatinine clear ance < 45 mL/min/1.73 m 2(as per Modification of Diet in Renal Disease equation), need for continuous RRT, death due to renal disease.
confirmed in long-term studies using clinical hard endpoints
[100]. Further renal data will also becomeavailable when the
resultsoftheongoingCVoutcometrial,Researching Cardiovascu-lar Events with a Weekly Incretin in Diabetes (REWIND), are published.
IntherecentlypublishedHarmonyOutcomestrial,albiglutide wassuperiortoplaceboasregardsmajorCVAEsinpatientswith T2DMandCVdisease(HR:0.78,95%CI:0.68–0.90;P=0.0006for superiority) [101]. A slight yet significant difference in eGFR betweenpatientsinthealbiglutidegroupandthoseintheplacebo groupwas noted at 8months( 1.11mL/min/1.73m2, 95% CI:
1.84to 0.39),buttendedtodisappearat16months( 0.43mL/ min/1.73m2, 95% CI: 1.26–0.41). No increased risk of severe
renalAEswasreportedwirhalbiglutide.Nootherrenalendpoint data,including changes in albuminuria, are availablefrom this trial.
Divergentresultshavebeenreportedinrecentmeta-analyses investigatingtheeffectsofGLP-1RAsonmicrovascular complica-tions. In the first meta-analysis of 51 trials to report valuable informationonrenalendpoints,GLP1-RAsloweredtheincidence ofnephropathy[Mantel–Haenszel(MH)oddsratio(OR):0.74,95% CI: 0.60–0.92; P=0.005], and was significantly different vs placebo, but not vs any other class of active comparators
[102].Inanothermeta-analysisof77randomizedtrialsinvolving
60,434T2DMpatients,treatmentwithGLP-1RAswasassociated withsignificantreductionsinall-causeandCVmortality,butwith no significantdecrease in risk of nephropathy (risk reduction: 0.866,95%CI:0.625–1.199;P=0.385)[103].Inyetanother meta-analysisof60studiesinvolving60,077T2DMpatients,GLP-1RAs marginally reduced UACR compared with placebo and other antidiabeticagents[weightedmeandifference(WMD): 2.55mg/ g,95% CI: 4.37 to 0.73, and 5.52mg/g, 95% CI: 10.89 to 0.16,respectively],butresultedinnoclinicallyrelevantchanges
ineGFR[104].Ofnote, asthecommerciallyavailableGLP-1RAs
maydifferbyarangeofproperties,whetherornotthereisaclass effectwhenconsideringcardiorenalprotectionremainsanopen question[105,106].
SGLT2inhibitors
SGLT2is exert their glucose-lowering effects by promoting glucosuria,aneffectthatalsoresultsinbody-weightandfat-mass reductions.Inadditiontotheseeffects,theyincreasenatriuresis andosmoticdiuresis,therebyloweringarterialbloodpressureand plasmaoverload[107],allfactorsthatmaycontributetobetterCV and renal outcomes and rates of mortality [108]. In addition, switching from low-dose thiazide diuretics to SGLT2is has improved various metabolic parameters(HbA1c, fastingplasma
glucose,serumuricacid,BMI,visceralfatarea)withoutaffecting bloodpressureinpatientswithT2DMandhypertension[109].
SGLT2iscertainlyrepresentthemostpromising pharmacologi-calclassofglucose-loweringagentsnotonlyforCVfactors,butalso forrenal protectionin T2DMpatients [21,110].In recentyears, numerousexcellentandextensive reviewsdevotedtothis topic havesummarizedtheirpreclinicalandclinicaldata,andprovided severalhypothesestoexplainthenephroprotectiveeffectsofthese newantidiabeticagents[18,19,21,111–115].SGLT2ieffectsonthe kidneyaremostlikely explained bymultiplepathwaysbeyond systemiceffectsviareductionsinbloodglucose,body-weightand bloodpressure.SGLT2isareassociatedwithreducedglomerular hyperfiltration,aneffectmediatedthroughincreasednatriuresis, andrestoredtubuloglomerularfeedbackindependentlyof glycae-miccontrol.Increasedsodiumandchloridedeliverytothemacula densa following SGLT2 inhibition results in activation of renal tubuloglomerular feedback,leading to afferentvasoconstriction
and attenuation of diabetes-induced renal hyperfiltration
[21,111]. This effect may explain the early decline in eGFR
commonlyobservedafterinitiationofSGLT2itherapy.Thisinitial dropisfollowedbyaslowerdeclineofeGFRthereaftercompared withplacebo,aneffectpresumablyexplainedbypreservationof glomerularintegrityduetoareductioninintraglomerularpressure
[21,111].Inaddition,SGLT2ismayimproverenaloxygenationand
cellular energy metabolism [21]while also reducing intrarenal inflammation [116],thereby slowing theprogression of kidney functiondecline.
Recent results for biomarkers have suggested that the albuminuria-lowering effect of SGLT2is may be the result of decreased intraglomerular pressure or less tubular cell injury possiblyrelatedtodecreasedinflammation[117]andperhapsalso linked to reduced activity of the intrarenal renin–angiotensin system[118].SGLT2isalsolowerserumuricacidlevels[119,120], anindependentriskfactorfordiminishedeGFRsinpatientswith
T2DM[121,122].
Because of their specific mechanism of action targeting the kidney,SGLT2islosepartoftheirglucose-loweringactivitywhen eGFR fallsto<45–60mL/min/1.73m2,which meansthattheir
useisnolongerindicatedandshouldbeinterruptediflevelsare belowthisthreshold[123,124].Nevertheless,the blood-pressure-loweringeffectsofSGLT2isappeartobemaintained[125,126],and reductions in both major CV events and mortality have been reported in subgroup analyses of T2DM patients with eGFRs<60mL/min/1.73m2inCVoutcometrials[127,128].
How-ever, even though SGLT2is consistently reduce systolic blood pressure[129],thisspecificeffectapparentlyplaysaminorrolein theimprovementofeitherCV[130]orrenal[131]outcomes.
In patients with T2DM at high CV risk recruited for the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 DiabetesMellitus Patients–Removing Excess Glucose (EMPA-REGOUTCOME)[120],empagliflozinwasassociatedwithslower progressionofkidneydisease,asreflectedbyreducedalbuminuria andasmallerdeclineineGFR,andlowerratesofclinicallyrelevant renalAEs,includingprogressiontoESRD,comparedwithplacebo whenaddedtostandardcare[132](Table4).Also,adetailed post-hocanalysissupportsbothshort-termandlong-termbenefitsof empagliflozin on UACR, irrespective of albuminuria status at baseline[133].Atweek12,theplacebo-adjustedgeometricmean ratioofUACRchangesfrombaselinewithempagliflozinwere 7% (P=0.013), 25%(P<0.0001)and 32%(P<0.0001)inpatients withnormoalbuminuria,microalbuminuriaand macroalbuminu-ria,respectively,andtheseUACRreductionsweremaintainedat 164weeks.Indeed,patientstreatedwithempagliflozinweremore likelytoexperiencesustainedimprovementsfrom microalbumi-nuria to normoalbuminuria (HR: 1.43, 95% CI: 1.22–1.67; P<0.0001)andfrommacroalbuminuriatomicroalbuminuriaor normoalbuminuria(HR:1.82,1.40to2.37;P<0.0001),andless likely toexperience sustaineddeteriorationfrom normoalbumi-nuriatomicroalbuminuriaormacroalbuminuria(HR:0.84,0.74to 0.95;P=0.0077)[133].Ofnote,reductionsinmajorCVeventsand mortalitywerealsoconsistentacrossbaselinecategoriesofeGFR
and UACR [127]. In patients with prevalent DKD at baseline
(2250 of the whole cohort of 7020 patients), empagliflozin compared withplacebo reduced the risks of CV death by 29% (HR:0.71,95%CI:0.5–0.98),all-causemortalityby24%(HR:0.76, 95%CI:0.59–0.99)andhospitalizationforheartfailureby39%(HR: 0.61, 95% CI: 0.42–0.87). The effects of empagliflozin on these outcomeswereconsistentacrossallbaselinecategoriesofeGFR
andUACR[127].
In the Canagliflozin Cardiovascular Assessment Study (CAN-VAS) Program, prespecified outcomes included a composite of sustainedandadjudicateddoublingofserumcreatinine,ESRDand death from renal causes, the individual components of this
composite outcome, annualreductions in eGFR and changesin
UACR [134,135]. The composite renal outcome presented less
frequentlyinthecanagliflozingroupcomparedwiththeplacebo group, with consistent findings across the prespecified patient subgroups.AnnualeGFRdeclineswereslower andmeanUACRs werelowerin participantstreated withcanagliflozinthanwith placebo.Afterarathershortmedianfollow-upof2.4years,onlya numerical trend for less progression to ESRD requiring renal replacementtherapywasnoted[135](TableIV).Renaloutcomes (HR:0.59,95%CI:0.44–0.79vs.HR:0.63,95%CI:0.39–1.02;P= 0.73forinteraction)weresimilarlyreducedinthesecondaryand primaryCVpreventioncohorts,respectively[136].Inaddition,the relativeeffectsonmostoftheCVandrenaloutcomesweresimilar acrossalleGFRsubgroups[128].
Canagliflozincomparedwithglimepirideslowedtheprogression ofrenaldiseaseover2yearsinpatientswithT2DMtogetherwith reductionsinalbuminuriaanddeclinesineGFRindependentlyofits glycaemiceffects[137].Theserenoprotectiveeffectsofcanagliflozin were confirmed in a 1-year open-label study of JapaneseT2DM patientswithCKD,whichalsoshowedareductionin tubulointers-titialmarkers[138].Thelarge-scaleongoingprospective Canagli-flozin and Renal Endpoints in Diabetes with Established NephropathyClinicalEvaluation(CREDENCE)comparestheefficacy and safety of canagliflozin vs. placebo in preventing clinically importantkidneyandCVoutcomes(primaryoutcomeisacomposite ofESRD, doublingof serumcreatinineand renalorCVdeath) in patientswithT2DMandestablishedCKD[139].Asimilarstudyis alsoongoingwithdapagliflozin[AStudytoEvaluatetheEffectof Dapagliflozin onRenalOutcomesandCardiovascularMortality in PatientswithChronicKidneyDisease(Dapa-CKD);ClinicalTrials.gov identifier: NCT03036150]to confirm andextend the preliminary positive results for albuminuria over 2 years with dapagliflozin therapyinT2DMpatientswithrenalimpairment[140].
Nevertheless,eventhoughSGLT2ishaveelicitedconsiderable enthusiasm,theymaybeassociatedwithAEs,someofwhichare potentiallysevere,therebyrequiringthatindividualbenefit–risk ratiosbetakenintoconsideration[141,142].Indeed,despitethe encouraging renal outcomesdescribed above, scattered reports havesuggestedthepossibleriskofacutekidneyinjurythatmay, onoccasions,requirerenalreplacementtherapy[143].Therefore, severalmechanismshavebeenproposedtoexplainthisriskwith SGLT2is,including:effectivevolumedepletion(withdehydration ordiuretictherapy);excessivedeclineintransglomerularpressure (with concomitant RAAS blockade); and induction of renal medullaryhypoxicinjury(triggeredby,forexample,non-steroidal anti-inflammatorydrugs)[123,142].Giventhehigherproportion ofreportsofacuterenalfailurewithSGLT2isintheUSFoodand Drug Administration Adverse Event Reporting System (FAERS) database[144],theFDAnowrequiresthatacutekidneyinjurybe listedasapotentialside-effectofSGLT2iswhilecautioningcareful prescription of these drugs with the other above-mentioned medications.
Intheevent,itisimperativetoascertainwhetherthereported acuterenal failurerepresents truestructuralkidneyinjury ora functionaldeclineineGFR[145].Theavailabledatasupportthe latter,especiallyincircumstancesexposingpatientsto dehydra-tion.IntheEMPA-REGOUTCOME,thenumberofpatients(mostly being treated with RAAS blockers) who developed acute renal failureappearedtobelessinthegrouptreatedwiththeSGLT2i thanwithplacebo[132].Infact,whenSGLT2isareproperlyusedin clinicalpractice,acutekidneyinjuryisarareevent.Inaddition,a network and cumulative meta-analysis of RCTs has provided diverse results for three SGLT2is regarding risk of renal AEs, therebyindicatingthatmoredatafromlargelong-termRCTsand well-conducted observational studies in real-life settings are clearlywarrantedbeforeanyconclusionscanbedrawn[146].
Table 4 Renal outcomes reported with sodium–glucose cotransporter type-2 inhibitors (SGLT2is) in patients with type 2 diabetes and high cardiovascular ri sk. Studies SGLT 2i daily dose vs. compar ator Active vs. placebo (n )
Median follow-up (years) Baseline mean eGFR Annual GFR decline (slope difference) Baseline UACR (g/g) Change in UACR (%)
New-onset persistent macro Doubling of serum creatinine Progression to ESRD requiring RRT Composite renal outcome Death from any cause a EMPA-REG OUTCOME [120,132,133] Empagliflo zin 10 or 25 mg vs. placebo 4687 vs. 2333 3.1 74.2 1.48 (NA), P < 0.001 Mic ro: 29%, macro: 11% Range: 15% to 49% b 0.62 (0.54–0.72), P< 0.001 0.56 (0.39–0.79), P< 0.001 0.45 (0.21–0.97), P = 0.04 0.61 c(0.53–0.70), P < 0.001 0.68 (0.57–0.82), P < 0 .001 CANVAS [134,135] Canagli flozin 100–300 mg vs. placebo 5795 vs. 4347 2.4 76.5 1.2 (1.0–1.4), NA Med ian: 11.3 (IQR: 6.5–33.0), micro or macro: 27% 18% ( 16 to 20), NA 0.73 (0.67–0.79) 0.50 (0.30 –0.84), NA 0.77 (0.30–1.97), NS 0.60 d(0.47–0.77), P < 0.001 0.87 (0.74–1.01), NS Results are expressed as haz ard ratios (95% confidence interval). eGFR: estimated glomerular filtration rate; UACR: urina ry albumin/creatinine ratio; ESRD: end -stage renal disease; NA: not available; IQR: interq uartile range; NS: not significant. a Includes rena l death, as those results are lacking in publications (presumably very few events). b Normoalbuminuria at baseline: 15%, 95% CI: 22 to 7, P = 0.0004; microalbuminuria (micro) at baseline: 42%, 95% CI: 49 to 34, P < 0.0001, macroalbuminuria (macro) at baseline: 49%, 95% CI: 60 to 36, P < 0.0001. c Progression to macro: doubling of serum creatinine , initiation of renal replacement therapy (RRT), death due to renal disease; another post-hoc out come was doubling of serum creatinine, initiation of RRT, death due to renal disease (HR: 0.54, 95% CI: 0.40–0.75, P < 0.001). d Sustained 40% reduction in eGFR, need for RRT, death due to renal causes; another composite endpoint was sustaine d doubling of serum creatinine, ESRD , death due to renal causes (HR: 0.53, 95% CI: 0.33–0.84).
Insulin
Surprisingly, few data have been published to support the nephroprotective effects of insulin in experimental preclinical studies,whichcontrastswiththeunexpectedinterestdevotedto C-peptidealmostadecadeago[147,148].Yet,severalkeyelements oftheinsulin-signallingcascadecontributetopodocytefunction and survival[149],and theinsulin receptor iscrucial for renal function in the glomeruli and tubules. When signalling is diminished in, for example, insulin-resistant states, it may be responsible for a number of important renal complications, includingglomerulardiseaseandalbuminuria,leadingto hyper-tension[150].Alsointriguingisthefactthattheeffectsofinsulin therapy on renal outcomes have been poorly investigated in patients withT2DM,and that thedatafromavailableRCTsare scarceanddifficulttointerpretforseveralreasons.IntheUKPDS, newlydiagnosedT2DMpatientswereatlowrenalrisk,andthe intensive group included sulphonylurea-treated and insulin-treatedpatients[151,152].IntheActiontoControlCardiovascular RiskinDiabetes(ACCORD)study,VeteransAffairsDiabetesTrial (VADT)andADVANCE,intensificationofbloodglucosecontrolwas based on more insulin therapy, but not exclusively, making it difficulttodifferentiatetheeffectsofreductionofhyperglycaemia fromthoseofinsulinperse[153].Finally,theOutcomeReduction withInitialGlargineIntervention(ORIGIN)trialincludedpatients with dysglycaemia, and renal outcomes were not analyzed separatelyfromeyedisease[154].
Few studies have provided data on renal endpoints when comparing insulintherapy with other glucose-lowering medica-tions,andnonehavesupportedbetternephroprotectionbyinsulin. In a retrospective cohort study usingdatafrom the UK General PracticeResearchDatabase,exogenousinsulintherapycompared withmetforminmonotherapyasthereferencewasassociatedwith anincreasedriskofdiabetes-relatedcomplications,includingrenal complications. However, differences in baseline characteristics between treatment groups (more advanced and complicated disease in insulin-treated patients) should be considered when interpretingtheseresults[155].Ofthepatientswhointensifiedtheir metformin monotherapy in the US Veterans Affairs national database,the additionofinsulincomparedwitha sulphonylurea wasnotassociatedwithalowerrateofadversekidneyoutcomes (persistenteGFRdecline35%frombaseline,adiagnosisofESRD). Incontrast,itwasassociatedwithahigherrateofthecomposite outcome,including death,whichwas not modified accordingto baselineeGFR[156].InthepreviouslymentionedAWARD-7trial, although insulinglargine was associated with a slightlygreater decline in eGFR compared with once-weekly dulaglutide at 52weeks,bothtreatmentsprovided similarglycaemiccontrolin patientswithT2DMandmoderate-to-severeDKD[98].InaUSstudy within a real-lifesetting, initiationof insulinglarginecompared withdulaglutidetherapywasassociatedwithasignificantlygreater decreaseineGFRafter1yeartogetherwithasmallerreductionin HbA1c [99]. Finally, in a study comparing basal insulin with pioglitazone asanadd-on therapyfor T2DM patients forwhom sulphonylureaandmetforminregimenshadfailed,bothtreatments improved glycaemic control, whereas only pioglitazone proved advantageousintermsofpreservingrenalfunction[58].
Combinedtherapies
DKDinT2DMisacomplexdisorderthatrequiresmultifactorial interventionstominimizetherisk,andRAASinhibitortherapyis themainstayofDKDprevention[6].InT2DMpatientsathighCV riskrecruitedforfourlargeprospectivetrialsshowingsignificant reductions in renal outcomes (LEADER, SUSTAIN-6, EMPA-REG
OUTCOME,CANVAS), almostthree-quartersofall patientswere treated with RAAS blockers. The potential complementary mechanism between RAAS inhibitors and SGLT2is has been emphasized,asdiscussedinarecentreview[157].
Whenfocusingonglucose-loweringtherapies,alargemajority ofpatients includedintheabove-mentionedtrialsweretreated withmetforminatbaselineandthroughoutthefollow-upperiod. Thus,liraglutide,semaglutide,empagliflozinorcanagliflozinwere added tothestandard carewhich, in mostpatients, comprised metformin; the latter, however, was prescribed at similar percentagesinboththetesteddrugandplacebogroups.
ApromisingcombinationistheassociationofanSGLT2iwitha GLP-1RA:theyappeartobesynergisticand,atleastaccordingto theavailableshort-termdataforeachpharmacologicalapproach, thiscombinationmayyetbethemostusefulwaytoprotectthe kidney(andheartaswell)inT2DMpatients[158].However,the strategy still requires further validation inclinical trialswitha focusonCVandrenaloutcomesbeforeitcanberecommendedfor moreextensiveuseinclinicalpractice,especiallyassuchadrug combinationismoreexpensive.Moreover,whethertheadditionof pioglitazonemightalsoresultinbetterrenaloutcomes,ashasbeen postulatedforCVoutcomes[159],remainsanopenquestion. Conclusion
TheoverallnumberofpatientswithDKDishighandisexpected tocontinuetoincreaseinparallelwiththegrowingglobalT2DM pandemic. Yet,based on some landmark clinical trials, DKD is preventablebycontrollingconventionalfactors,including hyper-glycaemia and hypertension, using a combination of lifestyle approachesand multifactorialdrugtherapies.Ofthe pharmaco-logicalapproaches,RAASinhibitorsareconsideredthecornerstone of renal protection, especially in T2DM patients with (micro)-albuminuria.Nevertheless,theremainingriskofDKDprogression isstillhigh.
Improvingglucosecontrolremainsessentialtoeitherprevent orslowtheprogressionofDKD.Yet,despitethenumerouspositive resultsinpreclinicalstudies,mostglucose-loweringagentshave only shown favourable effects on surrogate endpoints, such as albuminuria, in clinical studies, with almost no evidence of positiveeffectsonhardrenaloutcomes(Table1).Incontrast, GLP-1RAsandSGLT2ishaveproventheirabilitytoreducecomposite renaloutcomesincludingalbuminuria,eGFRdecline,doublingof creatinine and progression to ESRD or kidney-related death. However, only SGLT2is have proved capable of reducing hard clinicalendpoints,suchasdoublingofcreatinineandprogression toESRD,whilethepositiveeffectsofGLP-1RAsoncompositerenal outcomes were mainly driven by the reduction of new-onset macroalbuminuria.Thisiswhytheupdated2018consensusreport by the American Diabetes Association (ADA) and European Association fortheStudyofDiabetes(EASD)hasrecommended that,forpatientswithT2DMandCKDwithorwithoutCVdisease, thefirsttherapeuticoptionconsideredshouldbeanSGLT2ishown toreduceDKDprogressionor,ifcontraindicated(eGFRislessthan adequate) or not preferred, a GLP-1RA to exert CV protection
[160].Ofnote,asthesenephroprotectiveeffectsareindependentof
glucose-lowering,theunderlyingmechanismsremainasubjectof debate.Besidestheirpositiveeffectsonsystemicfactorssuchas blood glucose,body weightand blood pressure, GLP-1RAs and SGLT2isexerttheirnephroprotectionmainlyviadirectintrarenal effectsrelatedtohaemodynamicchangesortheir anti-inflamma-tory/antioxidative/antifibroticactivities.
Funding
Nosourcesoffundingwereusedtoassistinthepreparationofthismanuscript.No conflictsofinterestaredirectlyrelevanttothecontentofthismanuscript.
Disclosureofinterest
A.J. Scheen has received lecture/advisor fees from AstraZeneca, Boehringer Ingelheim,EliLilly,Janssen,MerckSharpandDohme, Novartis,NovoNordisk, SanofiandServier.HehasworkedasaclinicalinvestigatorintheTECOS,LEADER, EMPA-REGOUTCOME,HARMONY-OUTCOMESandCANVAS-Rtrials.
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