Long-term Benefits of IntensiveGlucose Control for PreventingEnd-Stage Kidney Disease:ADVANCE-ONDiabetes Care 2016;39:694–700 | DOI: 10.2337/dc15-2322

OBJECTIVE

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Con-trolled Evaluation (ADVANCE) trial reported that intensive glucose control pre-vents end-stage kidney disease (ESKD) in patients with type 2 diabetes, butuncertainty about the balance between risks and benefits exists. Here, we exam-ine the long-term effects of intensive glucose control on risk of ESKD and otheroutcomes.

RESEARCH DESIGN AND METHODS

Survivors, previously randomized to intensive or standard glucose control, wereinvited to participate in post-trial follow-up. ESKD, defined as the need for dialysisor kidney transplantation, or death due to kidney disease, was documentedoverall and by baseline CKD stage, along with hypoglycemic episodes, majorcardiovascular events, and death from other causes.

RESULTS

A total of 8,494 ADVANCE participants were followed for a median of 5.4 addi-tional years. In-trial HbA1c differences disappeared by the first post-trial visit. Thein-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35,P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54,P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lowerbaseline systolic blood pressure levels (P = 0.01). The effects of glucose loweringon the risks of death, cardiovascular death, or major cardiovascular events did notdiffer by levels of kidney function (P > 0.26).

CONCLUSIONS

Intensive glucose control was associated with a long-term reduction in ESKD,without evidence of any increased risk of cardiovascular events or death. Thesebenefits were greater with preserved kidney function and with well-controlledblood pressure.

Diabetes has surpassed glomerulonephritis as the commonest cause of end-stagekidney disease (ESKD) in the developed world and many developing countries (1).Although only a minority of individuals with diabetes will develop nephropathy andESKD, the rapidly increasing number of people with type 2 diabetes is projected toresult in a substantial increase in the numbers requiring renal replacement therapy,in turn leading tomajor growth in economic costs for health systems (2). In addition,

1The George Institute for Global Health, Univer-sity of Sydney, Sydney, Australia2The George Institute for Global Health, Univer-sity of Oxford, Oxford, U.K.3Department of Epidemiology, Johns HopkinsUniversity, Baltimore, MD4Baker IDI Heart and Diabetes Institute, Mel-bourne, Australia5Centre hospitalier de l`Universite de Montreal,Montreal, Canada6Royal Melbourne Hospital, University of Mel-bourne, Melbourne, Australia7University of Sheffield and Sheffield TeachingHospitals, National Health Service FoundationTrust, Sheffield, U.K.8Policlinico diMonzaand IRCCS IstitutoAuxologicoItaliano, University of Milano-Bicocca, Milan, Italy9Hopital Bichat-Claude Bernard and UniversiteParis 7, Paris, France10Oxford Centre for Diabetes, Endocrinology andMetabolism, University of Oxford, Oxford, U.K.11International Centre for Circulatory Health,National Heart and Lung Institute, ImperialCollege London, London, U.K.12Institute of Cardiovascular Science, UniversityCollege, London, U.K.13School of Public Health and Preventative Med-icine, Monash University, Melbourne, Australia

Corresponding author: Vlado Perkovic, vperkovic@georgeinstitute.org.au, or Sophia Zoungas,szoungas@georgeinstitute.org.au.

Received 25 October 2015 and accepted 9January 2016.

Clinical trial reg. no. NCT00949286, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-2322/-/DC1.

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

See accompanying articles, pp. 664,668, 677, 686, 701, 709, 717, 726, 735,and 738.

Muh Geot Wong,1 Vlado Perkovic,1

John Chalmers,1 Mark Woodward,1,2,3

Qiang Li,1 Mark E. Cooper,4 Pavel Hamet,5

Stephen Harrap,6 Simon Heller,7

Stephen MacMahon,1,2

Giuseppe Mancia,8 Michel Marre,9

David Matthews,10 Bruce Neal,1,11

Neil Poulter,11 Anthony Rodgers,1

Bryan Williams,12 and Sophia Zoungas,1,13

for the ADVANCE-ON Collaborative Group

694 Diabetes Care Volume 39, May 2016

CARDIOVASC

ULA

RDISEA

SEANDDIABETES

chronic kidney disease (CKD) is recog-nized as one of the strongest risk factorsfor cardiovascular disease, particularlyin the presence of diabetes, conferring asubstantial increase in the risk of deathand hospitalization (3).Despite the implementation of “best

practice” standards of care for lifestylemodification, blood pressure lowering,and renin-angiotensin-aldosterone sys-tem blockade, there remains a high levelof progression to ESKD for those withdiabetic kidney disease (4,5). Although anumber of promising novel therapies arebeing studied in early clinical trials, noneare as yet available (6). This has resultedin renewed interest in the role of inten-sive glucose control. Post-trial follow-upof the UK Prospective Diabetes Study(UKPDS) cohort of newly diagnosed pa-tients with type 2 diabetes (7) and theDiabetes Control and Complications Trial(DCCT) cohort of young patients withtype 1 diabetes (8) showed a sustainedbenefit for microvascular complications,beyond the period of intensive glucosecontrol. In these studies, microvascularcomplications were composites of retinalphotocoagulation, microalbuminuria, andneuropathy, with few, if any, patientsdeveloping ESKD or dying from renaldisease (9).We previously reported, in the Action

inDiabetes andVascular Disease: Preteraxand DiamicronMR Controlled Evaluation(ADVANCE) study, that intensive glucosecontrol in patients with type 2 diabetessignificantly reduced the risk of a rangeof renal outcomes including new or wors-ening nephropathy and ESKD (10). How-ever, the small number of ESKD eventsobserved during the trial limited thestrength of the conclusions. In addition,the safety of intensive glucose controlin the presence of CKD has been ques-tioned, with the Action to Control Car-diovascular Risk in Diabetes (ACCORD)trial (11) recently reporting that its inten-sive glucose-lowering strategy increasedthe risk of cardiovascular and all-causedeath among participants with CKDbut not in those with normal kidneyfunction.The outcomes of the 6-year post-trial

follow-upof theADVANCE trial cohort, alsoknown as the ADVANCE-ObservatioNal(ADVANCE-ON) study, were recently pub-lished (12). Here, we report on furtheranalyses that examine the long-termeffects of the intensive glucose control

strategy on ESKD, cardiovascular events,and death, including analyses acrossdifferent levels of kidney function, inpatients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

ADVANCE TrialThe original trial design and methodshave previously been published (13,14).Briefly, 11,140 individuals with type 2diabetes aged 55 years or older, with atleast one additional risk factor for cardio-vascular disease, were enrolled from 215centers in 20 countries between 2001and 2003. Patients were randomlyassigned in a 2 3 2 factorial design to1) a gliclazide modified-release (MR)–based intensive glucose control regimen,aiming for an HbA1c level of 6.5% orlower, or to standard glucose controlbased on local guidelines of participatingcountries, and 2) a single pill (fixed dose)combinationofperindopril and indapamide(4 mg and 1.25 mg, respectively) ormatching placebo, after a 6-week activerun-in period. The last trial visits for theglucose control comparison were com-pleted in January 2008, after a medianfollow-up period of 5.0 years, and theresults for the blood pressure (13) andglucose (14) interventions were reportedthen. All patients then ceased the ran-domized interventions and returnedto usual care through their treatingphysician.

ADVANCE-ON StudyADVANCE-ON was a post-trial follow-up study of surviving ADVANCE trialpatients.

All local ADVANCE trial sites were in-vited to participate in ADVANCE-ON,and 172 of 215 sites (80%) agreed. Afterapproval by the local ethics reviewboards of each participating site, all sur-viving trial patients at those sites wereinvited to enter post-trial follow-up. InJanuary 2010, annual post-trial visitscommenced. At the first post-trial visit,informed consent was obtained and astandardized questionnaire completedon the occurrence of all study outcomesof interest and all medications taken. Arandom subset of 2,000 patients, bal-anced across regions and across theprior randomized treatment arms, wasalso invited to undergo assessment ofHbA1c, fasting blood glucose, bloodpressure, weight, serum creatinine,and urinary albumin-to-creatinine ratio

at the first post-trial visit to determinewhether in-trial differences persisted.For patients known to have died afterthe final in-trial visit, the cause anddate of death were recorded. For pa-tients unwilling or unable to attendstudy visits in person, follow-up wasconducted by telephone or home visit,or information was provided by the pri-mary care physician, other health careproviders, or next of kin. At annual visits,patients completed a questionnaire onmedication taken and the occurrence ofstudy outcomes. In addition, at the finalvisits, that occurred between 1 January2013 and 28 February 2014, patients at-tending visits in person (whether or notthey had completed assessment at thefirst visit) were invited to undergo reas-sessment of HbA1c, fasting blood glucose,weight, blood pressure, serumcreatinine,and urinary albumin-to-creatinine ratio.

Study OutcomesThe prespecified renal outcomes forADVANCE-ON were ESKD (requirementfor dialysis or renal transplantation) anddeath due to renal disease. Other out-comes included death due to any cause,major cardiovascular events (myocardialinfarction, stroke, or cardiovasculardeath, examined jointly and separately),and major hypoglycemia. It was notpossible to replicate the outcome“new or worsening nephropathy” as de-fined in the original trial (developmentof macroalbuminuria [urinary albumin-to-creatinine ratio .300 mg/mg or33.9 mg/mmol/L], doubling of serumcreatinine to a level of 200 mmol/L[2.26 mg/dL], ESKD, and death due torenal disease) because levels of serumcreatinine and urinary albumin wereonly measured in a subgroup of patientsduring post-trial follow-up. Outcomesoccurring during post-trial follow-upwere as reported by the study centers us-ing the standardized definitions used dur-ing the trial, without central adjudication.

Statistical MethodsAnalyses were conducted according tothe initial treatment assignment. Treat-ment effects were examined usingcumulative incidence survival curvesand Cox proportional hazards models.Patients were censored at the first rele-vant end point: the date of death, dateof last visit (for those still alive), or datelast known to be alive for those whose

care.diabetesjournals.org Wong and Associates 695

vital status was unknown at the end ofthe study (28 February 2014). Hazardratios (HRs) were estimated for the in-trial period and over the entire period offollow-up. An additional post hoc obser-vational analysis was performed for thepost-trial period alone. Serial HRs with95% CIs were estimated at the endof each calendar year of post-trial fol-low-up. The homogeneity of treatmenteffects for prespecified subgroups wastested by adding an interaction term tothe relevant Cox models.The Chronic Kidney Disease–Epidemi-

ology Collaboration (CKD-EPI) equationwas used to calculate the estimatedglomerular filtration rate (eGFR). Foranalyses by baseline CKD status, partic-ipants were divided into those with CKDstage 1 (eGFR $90 mL/min/1.73 m2

and urinary albumin-to-creatinine ratio$30 mg/mg), CKD stage 2 (eGFR be-tween 60 and 89 mL/min/1.73 m2 andurinary albumin-to-creatinine ratio$30 mg/mg), and CKD stage $3 (eGFR,60 mL/min/1.73 m2 with or withoutalbuminuria and those without CKD (eGFR$60mL/min/1.73m2 and urinary albumin-to-creatinine ratio,30 mg/mg) (15).The analyses were performed with

SAS (version 9.2). All tests were two-sided, and P values ,0.05 were consid-ered to indicate statistical significance.The protocol prespecified that noadjustments would be made for themultiple statistical testing (12). In lightof this, the findings were interpretedwith the appropriate degree of caution.

RESULTS

Of 10,082 patients originally assigned tothe randomized treatments and alive atthe end of the trial, 8,494 (4,283 vs. 4,211for intensive vs. standard glucose control,respectively) entered post-trial follow-upand 5,131 (2,638 vs. 2,493) of those stillalive completed a visit during the finalyear of the study (12). Themedian in-trial,post-trial, and total follow-up periodswere 5.0 years, 5.4 years, and 9.9 years,respectively (Supplementary Fig. 1). Aspreviously reported, the prerandomiza-tion characteristics of the original glu-cose control trial population and of thefollow-up study cohort were similar (16).

Use of Glucose-Lowering and OtherTherapiesDuring post-trial follow-up, there wasless use of sulfonylureas (including

gliclazide modified release), metformin,glitazones, and a-glucosidase inhibitorsbut more use of insulin and other glu-cose-lowering therapies (including glip-tins and glucagon-like peptide 1 analogs)in both the intensive and standardglucose control groups, irrespective ofCKD stage (Supplementary Tables 1–3).The use of blood pressure–loweringagents, statins, and antiplatelet agentswas also comparable across the groups, ir-respectiveof theCKDstage (SupplementaryTables 1–3).

Glycemic ControlThe mean difference in HbA1c (0.67%[95% CI 0.64, 0.70], P, 0.001) observedat the end of randomized therapy waslost when measured on average 2.9years later at the first post-trial visit(0.08% [95% CI 20.07, 0.22], P = 0.29).Therewas a rise in HbA1c in the intensivecontrol group approaching that ob-served in the standard control group.The HbA1c levels of the two groups con-verged at the first post-trial visit (7.3%vs. 7.3%, P = 0.29) and remained similarat the last post-trial visit (12).

ESKD or Renal DeathDuring the in-trial period, 27 patientsrecorded ESKD events and 37 patientsdied due to renal causes. During thepost-trial period, an additional 55 pa-tients recorded ESKD events and 64 pa-tients died due to renal causes (Table 1).

The significant reduction in the risk ofESKD observed with intensive glucosecontrol during the in-trial period (7 vs.20 events, HR 0.35 [95% CI 0.15, 0.83],P = 0.02) persisted after a total of 9.9years of follow-up (29 vs. 53, HR 0.54[95% CI 0.34, 0.85], P , 0.01) (Fig. 1).

Subgroup analyses examining the ef-fects of intensive glucose control by pa-tient characteristics at trial baselinesuggested no heterogeneity with similarrisk reductions for males and females,those aged above and below 65 years,and those with HbA1c levels above andbelow the median (7.2%) (Fig. 2).

In contrast, heterogeneity was ob-served for patients according to CKDstage, as well as patients with systolicblood pressure (SBP) levels belowor above 140 mmHg (Fig. 2, both P ,0.05). A graded reduction in thestrength of the effect of intensive glu-cose control on ESKD was seen as CKDstage increased (Fig. 2) (Pheterogeneity = 0.04).

In patients at trial baseline with SBP levels,140 mmHg, the risk reduction in ESKDwas greater than in those with SBP levels.140 mmHg (HR 0.19 [95% CI 0.06, 0.55]vs.HR0.77 [95%CI0.46, 1.30], respectively,Pheterogeneity = 0.01) (Fig. 2).

The nonsignificant effect on the riskof death due to renal disease observedduring the in-trial period (HR 0.85 [95%CI 0.45, 1.62]) remained similar after atotal of 9.9 years of follow-up (HR 0.89[95% CI 0.60, 1.31]) (Fig. 1).

Absolute Renal EffectsAcross the entire population over 9.9years, 194 participants would need tobe treated with intensive glucose con-trol to prevent one ESKD event (Table1). Further, the number that wouldneed to be treated (NNT) by CKD stagewas 109 for CKD stages 1 and 2 and393 for CKD stage 3 or greater. TheNNT by SBP was 120 for baseline SBP,140 mmHg and 368 for baseline SBP$140 mmHg (Table 1).

Other OutcomesThe rate of major hypoglycemia was lowoverall, and the increase in risk for theintensive versus the standard glucosecontrol group observed during the trialwas no longer evident after post-trialfollow-up (Supplementary Fig. 2). Theabsolute risk of hypoglycemia tendedto be slightly higher for the group withCKD stage 3 or greater compared withno CKD or CKD stage 1 and 2 irrespectiveof the original randomized groups. How-ever, the increase in risk for the inten-sive versus standard glucose controlgroups was similarly no longer evidentfor subgroups of patients defined byCKD stage after post-trial follow-up(overall study period Pheterogeneity =0.92).

Intensive glucose control had no cleareffects on overall all-cause mortality,cardiovascular death, major cardiovas-cular events, myocardial infarction, orstroke. In addition, there was no evi-dence that baseline CKD status had anyimpact on the effect of intensiveglucose control on these outcomes(Fig. 3) (all Pheterogeneity . 0.2) duringthe in-trial period or during extendedfollow-up.

CONCLUSIONS

After following the ADVANCE trial co-hort for a total of 9.9 years, we showthat a prior period of intensive glucose

696 Long-term Benefits of Glucose Control on ESKD Diabetes Care Volume 39, May 2016

control continues to protect against thedevelopment of ESKD in patients withtype 2 diabetes. The patients who ap-pear to benefit the most are thosewith preserved kidney function, with in-termediate effects in the group withCKD stage 1 or 2 and lesser effects inparticipants with CKD stage 3 or greaterat baseline. Greater reductions in ESKDwere also observed in participantswith better blood pressure control at

baseline (SBP ,140 mmHg). Impor-tantly, the impact of intensive glucosecontrol on mortality or major cardiovas-cular events was not adversely affectedby CKD at baseline during either the trialor overall study follow-up.

Our data provide the strongest evi-dence to date regarding the renal bene-fits of intensive glucose lowering andare consistent with data on intermedi-ate outcomes from other studies. These

include the Epidemiology of Diabetes In-terventions and Complications (EDIC)study in a population of younger individ-uals with type 1 diabetes, which reportedthat a prior period of intensive glucosecontrol reduced the long-term risk ofdeveloping renal impairment (eGFR ,60mL/min/1.73 m2) by 50% after a medianfollow-up of 22 years (17). However, inthat study a clear benefit for ESKD wasnot demonstrated, most likely because

Table 1—Comparison of NNT over 5 years and 9.9 years to prevent one ESKD event overall

Population andsubgroup

5-Year follow-up period 9.9-Year follow-up period

Participants,N (%)

Annual event rateNNT to preventone ESKD eventover 5 years

Participants,N (%)

Annual event rateNNT to preventone ESKD over

9.9 yearsStandard,

%Intensive,

%Standard,

%Intensive,

%

Overall 11,140 (100) 0.075 0.026 410 11,140 (100) 0.112 0.061 194

No CKD 5,935 (53.3) 0.014 0.007 2,839 5,935 (53.3) 0.046 0.008 259

CKD stages 1 and 2 2,404 (21.6) 0.106 0.035 283 2,404 (21.6) 0.14 0.048 109

CKD stage $3 2,256 (20.3) 0.129 0.039 220 2,256 (20.3) 0.232 0.207 393

SBP ,140 mmHg 4,704 (42.2) 0.053 0.009 453 4,704 (42.2) 0.103 0.019 120

SBP $140 mmHg 6,435 (57.8) 0.091 0.039 384 6,435 (57.8) 0.12 0.092 368

NNT over 5 years = 1/(annual event rate in standard 3 5 2 annual event rate in intensive 3 5). NNT over 10 years = 1/(annual event rate instandard 3 10 2 annual event rate in intensive 3 10). Stage 1 CKD was defined as eGFR $90 mL/min/1.73 m2 and urinary albumin-to-creatinineratio$30 mg/mg; stage 2 CKD was defined as eGFR between 60 and 89 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio$30 mg/mg; stage$3 was defined as eGFR ,60 mL/min/1.73 m2 with or without albuminuria. Mild CKD included patients with stages 1 and 2 and moderate CKDincluded patients with stage 3 CKD. eGFR is calculated using the EPI-CKD formula.

Figure 1—Summary plot showing the effects of intensive glucose lowering compared with standard glucose lowering on ESKD and/or death due torenal cause during the in-trial, post-trial, and overall study periods of follow-up. Renal death, death due to renal causes.

care.diabetesjournals.org Wong and Associates 697

Figure 2—Subgroup analyses by baseline characteristics for the outcome of ESKD. The P value provided represents test for heterogeneity betweensubgroups. ARB, angiotensin receptor blocker; BP, blood pressure.

698 Long-term Benefits of Glucose Control on ESKD Diabetes Care Volume 39, May 2016

few ESKD events were recorded. Simi-larly the long-term follow-up of theUKPDS cohort of patients newly diag-nosed with type 2 diabetes reportedpersistent microvascular (eye and renalevents) and emerging macrovascularbenefits in those previously assigned tointensive glucose lowering, with bene-fits for kidney failure defined by lowerrisk of increases in serum creatinineto .250 mmol/L. The ACCORD studyreported a numerically lower risk of re-nal failure with intensive glucose lower-ing; however, this did not achievestatistical significance (18). The resultsregarding the effects on ESKD in thelong-term follow-up of the ACCORD trialare awaited with interest.In ADVANCE, the difference in the

rate of ESKD events between the inten-sive and the standard glucose controlgroups took .2 years to emerge butthen persisted (with a further numeri-cally lower number of events) to theend of the overall study period, evenafter the HbA1c converged. The riskreduction for ESKD events observed inADVANCE-ON likely goes beyond a sim-ple carry forward of the effects ob-served during the original trial period.

As the development of ESKD often takesdecades to appear after the onset of di-abetes, it might well be anticipated thatslowing of this process would take yearsto become evident, especially if it re-quires abrogation of diabetes-inducedstructural changes in the glomerulus(19,20). In contrast, the effects ofrenin-angiotensin-aldosterone systemblockade and blood pressure loweringare likely to have a more rapid onsetand offset in response to treatment.

Our results highlight the importanceof commencing intensive glucose con-trol before diabetic kidney disease de-velops, as lesser renal benefit wasobserved in participants with an estab-lished reduction in kidney function, sug-gesting that the relative contribution ofglucose-dependent and glucose-inde-pendent pathways may vary at differentlevels of kidney function. The lesser ben-efit in those with moderately reducedkidney function (CKD stage 3 or greater)may indicate that glucose-independentmechanisms of renal progression arepredominant in the later stages of thedisease (21). In the subgroup of patientswithout baseline CKD, the benefits forESKD were maintained in the long

term, suggesting the earlier period ofintensive glucose control may have pre-vented structural changes in both theglomeruli and tubulointerstitium, whenrenal function was relatively intact.

Similar differences were found in sub-groups defined by baseline blood pres-sure, with a much greater reduction inESKD by the end of overall follow-up inparticipants with SBP at baseline belowthe hypertensive range (,140 mmHg).These findings also support the premisethat greater benefits will be obtainedthrough intensive glucose control ear-lier in the life course of the patientwith type 2 diabetes. While a recent re-port has raised concerns regarding apossible increase in the risk of adverseoutcomes in the presence of CKD withintensive glucose control, particularlyrisk of death (11), we found no evidencefor this. Collectively, these data supportearly intensive glucose control andoptimalblood pressure levels for the prevention oflong-term renal complications in individu-als with type 2 diabetes.

An interesting finding was the lack ofconsistency in the results for ESKD andrenal death. A low number of events isone reason. Death purely attributed to

Figure 3—Forest plots of all-cause mortality and major cardiovascular events by randomized subgroups for the in-trial period (A) and overall studyperiod (B). The P value provided represents a test for heterogeneity between subgroups. MI, myocardial infarction.

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renal causes is less common than deathdue to cardiovascular or cerebrovascu-lar causes. However, establishing causeof death during any clinical trial may bechallenging. During the ADVANCE trial,renal death was adjudicated, whereasduring the ADVANCE-ON post-trial fol-low-up renal death could not be adjudi-cated. In addition, it may be difficult toascertain whether a death is due to pro-gressive kidney failure, intercurrent car-diovascular event, or some combinationof the two. This could result in greateruncertainty as to the effects on this out-come compared with that of ESKD, whichis simpler to define as requirement fordialysis or renal transplantation. Indeed,other clinical trials such as Reduction ofEndpoints inNIDDMwith the AngiotensinII Antagonist Losartan (RENAAL) and theIrbesartan Diabetic Nephropathy Trial(IDNT) have similarly not been able toidentify beneficial effects regarding re-nal death (4,5). It was also not possibleto report progression or regression ofalbuminuria or doubling of serum creat-inine as occurred in the original trial be-cause serum creatinine levels andurinary albumin-to-creatinine ratios atthe first post-trial visit were only avail-able and able to be collected for a subsetof participants (13).A clear strength of this study is the long-

term follow-up of a large and diverse pa-tient populationwith type 2 diabetes. Thelimitations include nonadjudicated renalend points and the lack of complete bio-chemical data for all participants duringthe post-trial follow-up. Additionally, al-though the number of ESKD events tripledduring the post-trial period, the numberof events remained small. This limitationis especially important to bear in mindwhen interpreting differences betweensubgroups and between stages of CKD.Our data build on a growing body of

evidence indicating an important rolefor intensive glucose control in limitingthe progression of kidney disease and incurbing the growing number of patientsaround the world with type 2 diabetesrequiring dialysis or transplantation as aresult of diabetic kidney disease.

Funding and Duality of Interest. TheADVANCE trial and ADVANCE-ON follow-upstudy were funded by unrestricted grants fromServier and the Australia National Health andMedical Research Council. M.G.W. reports fees

for scientific lectures from AstraZeneca. V.P.reports honoraria for scientific lectures fromBoehringer Ingelheim, Merck, AbbVie, Roche,AstraZeneca, and Servier and serves on steeringcommittees and/or advisory boards supportedbyAbbVie,Astellas, Baxter, Boehringer Ingelheim,Bristol-Myers Squibb, GlaxoSmithKline, Janssen,and Pfizer. J.C. reports research grants adminis-tered through the University of Sydney for theADVANCE trial and the ADVANCE-ON post-trial study and honoraria from Servier forspeaking about these studies at scientific meet-ings. P.H. is a member of College Internationalde Recherche Servier. B.W. has received hono-raria from Servier for lectures at scientificmeet-ings. S.Z. reports past participation in advisoryboards and/or receiving honoraria from AmgenAustralia, AstraZeneca/Bristol-Myers SquibbAustralia, Janssen-Cilag, Merck Sharp & Dohme(Australia), Novartis Australia, Sanofi, ServierLaboratories, and Takeda Australia as well asMonash University undertaking contract workfor AstraZeneca Pty Ltd./Bristol-Myers SquibbAustralia Pty Ltd. No other potential conflictsof interest relevant to this article were reported.Author Contributions.M.G.W. wrote the firstdraft of themanuscript. V.P., J.C., M.W., and S.Z.conceived the study protocol and analysis plan,researched data, and reviewed and editedthe manuscript. Q.L. completed all statistical anal-ysis.M.E.C., P.H., S.Ha., S.He., S.M., G.M., M.M.,D.M., B.N., N.P., A.R., and B.W. contributed todiscussion and reviewed and edited the manuscript.Prior Presentation. Parts of this study werepresented in abstract form at the InternationalDiabetes Federation 23rd World Diabetes Con-gress, Vancouver, BC, Canada, 30 November–4December 2015.

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700 Long-term Benefits of Glucose Control on ESKD Diabetes Care Volume 39, May 2016