694 Diabetes Care Volume 39, May 2016

Muh Geot Wong,1 Vlado Perkovic,1 Long-term Benefits of Intensive John Chalmers,1 Mark Woodward,1,2,3 Qiang Li,1 Mark E. Cooper,4 Pavel Hamet,5 Glucose Control for Preventing Stephen Harrap,6 Simon Heller,7 CARDIOVASCULAR DISEASE AND DIABETES Stephen MacMahon,1,2 End-Stage Disease: Giuseppe Mancia,8 Michel Marre,9 David Matthews,10 Bruce Neal,1,11 ADVANCE-ON Neil Poulter,11 Anthony Rodgers,1 12 1,13 Diabetes Care 2016;39:694–700 | DOI: 10.2337/dc15-2322 Bryan Williams, and Sophia Zoungas, for the ADVANCE-ON Collaborative Group

1The George Institute for Global Health, Univer- OBJECTIVE sity of Sydney, Sydney, Australia 2The George Institute for Global Health, Univer- The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Con- sity of Oxford, Oxford, U.K. trolled Evaluation (ADVANCE) trial reported that intensive glucose control pre- 3Department of , Johns Hopkins University, Baltimore, MD vents end-stage (ESKD) in patients with type 2 diabetes, but 4 fi Baker IDI Heart and Diabetes Institute, Mel- uncertainty about the balance between risks and bene ts exists. Here, we exam- bourne, Australia ine the long-term effects of intensive glucose control on risk of ESKD and other 5Centre hospitalier de l`Universite de Montreal, outcomes. Montreal, Canada 6Royal Melbourne Hospital, University of Mel- RESEARCH DESIGN AND METHODS bourne, Melbourne, Australia 7University of Sheffield and Sheffield Teaching Survivors, previously randomized to intensive or standard glucose control, were Hospitals, National Health Service Foundation invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis Trust, Sheffield, U.K. or kidney transplantation, or death due to kidney disease, was documented 8Policlinico di Monza and IRCCS Istituto Auxologico overall and by baseline CKD stage, along with hypoglycemic episodes, major Italiano, University of Milano-Bicocca, Milan, Italy 9Hopitalˆ Bichat-Claude Bernard and Universite´ cardiovascular events, and death from other causes. Paris 7, Paris, France 10Oxford Centre for Diabetes, Endocrinology and RESULTS Metabolism, University of Oxford, Oxford, U.K. A total of 8,494 ADVANCE participants were followed for a median of 5.4 addi- 11International Centre for Circulatory Health, tional years. In-trial HbA differences disappeared by the first post-trial visit. The National Heart and Lung Institute, Imperial 1c College London, London, U.K. in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, 12Institute of Cardiovascular Science, University P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, College, London, U.K. P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower 13School of Public Health and Preventative Med- baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering icine, Monash University, Melbourne, Australia on the risks of death, cardiovascular death, or major cardiovascular events did not Corresponding author: Vlado Perkovic, vperkovic@ P > georgeinstitute.org.au, or Sophia Zoungas, differ by levels of kidney function ( 0.26). [email protected]. CONCLUSIONS Received 25 October 2015 and accepted 9 January 2016. Intensive glucose control was associated with a long-term reduction in ESKD, reg. no. NCT00949286, clinicaltrials without evidence of any increased risk of cardiovascular events or death. These .gov. benefits were greater with preserved kidney function and with well-controlled This article contains Supplementary Data online blood pressure. at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc15-2322/-/DC1. © 2016 by the American Diabetes Association. Diabetes has surpassed glomerulonephritis as the commonest cause of end-stage Readers may use this article as long as the work is kidney disease (ESKD) in the developed world and many developing countries (1). properly cited, the use is educational and not for Although only a minority of individuals with diabetes will develop nephropathy and profit, and the work is not altered. ESKD, the rapidly increasing number of people with type 2 diabetes is projected to See accompanying articles, pp. 664, result in a substantial increase in the numbers requiring renal replacement therapy, 668, 677, 686, 701, 709, 717, 726, 735, in turn leading to major growth in economic costs for health systems (2). In addition, and 738. care.diabetesjournals.org Wong and Associates 695

chronic kidney disease (CKD) is recog- strategy on ESKD, cardiovascular events, at the first post-trial visit to determine nized as one of the strongest risk factors and death, including analyses across whether in-trial differences persisted. for cardiovascular disease, particularly different levels of kidney function, in For patients known to have died after in the presence of diabetes, conferring a patients with type 2 diabetes. the final in-trial visit, the cause and substantial increase in the risk of death date of death were recorded. For pa- and hospitalization (3). RESEARCH DESIGN AND METHODS tients unwilling or unable to attend Despite the implementation of “best ADVANCE Trial study visits in person, follow-up was practice” standards of care for lifestyle The original trial design and methods conducted by telephone or home visit, modification, blood pressure lowering, have previously been published (13,14). or information was provided by the pri- and renin-angiotensin-aldosterone sys- Briefly, 11,140 individuals with type 2 mary care physician, other health care tem blockade, there remains a high level diabetes aged 55 years or older, with at providers, or next of kin. At annual visits, of progression to ESKD for those with least one additional risk factor for cardio- patients completed a questionnaire on diabetic kidney disease (4,5). Although a vascular disease, were enrolled from 215 medication taken and the occurrence of number of promising novel therapies are centers in 20 countries between 2001 study outcomes. In addition, at the final being studied in early clinical trials, none and 2003. Patients were randomly visits, that occurred between 1 January are as yet available (6). This has resulted assigned in a 2 3 2 factorial design to 2013 and 28 February 2014, patients at- in renewed interest in the role of inten- 1) a gliclazide modified-release (MR)– tending visits in person (whether or not sive glucose control. Post-trial follow-up based intensive glucose control regimen, they had completed assessment at the fi of the UK Prospective Diabetes Study aiming for an HbA1c level of 6.5% or rst visit) were invited to undergo reas- (UKPDS) cohort of newly diagnosed pa- lower, or to standard glucose control sessment of HbA1c, fasting blood glucose, tients with type 2 diabetes (7) and the based on local guidelines of participating weight, blood pressure, serum creatinine, Diabetes Control and Complications Trial countries, and 2) a single pill (fixed dose) and urinary albumin-to-creatinine ratio. (DCCT) cohort of young patients with combination of perindopril and indapamide type 1 diabetes (8) showed a sustained (4 mg and 1.25 mg, respectively) or Study Outcomes benefit for microvascular complications, matching placebo, after a 6-week active The prespecified renal outcomes for beyond the period of intensive glucose run-in period. The last trial visits for the ADVANCE-ON were ESKD (requirement control. In these studies, microvascular glucose control comparison were com- for dialysis or renal transplantation) and complications were composites of retinal pleted in January 2008, after a median death due to renal disease. Other out- photocoagulation, microalbuminuria, and follow-up period of 5.0 years, and the comes included death due to any cause, neuropathy, with few, if any, patients results for the blood pressure (13) and major cardiovascular events (myocardial developing ESKD or dying from renal glucose (14) interventions were reported infarction, stroke, or cardiovascular disease (9). then. All patients then ceased the ran- death, examined jointly and separately), We previously reported, in the Action domized interventions and returned and major hypoglycemia. It was not in Diabetes and Vascular Disease: Preterax to usual care through their treating possible to replicate the outcome and Diamicron MR Controlled Evaluation physician. “new or worsening nephropathy” as de- (ADVANCE) study, that intensive glucose fined in the original trial (development control in patients with type 2 diabetes ADVANCE-ON Study of macroalbuminuria [urinary albumin- significantly reduced the risk of a range ADVANCE-ON was a post-trial follow- to-creatinine ratio .300 mg/mg or of renal outcomes including new or wors- up study of surviving ADVANCE trial 33.9 mg/mmol/L], doubling of serum ening nephropathy and ESKD (10). How- patients. creatinine to a level of 200 mmol/L ever, the small number of ESKD events All local ADVANCE trial sites were in- [2.26 mg/dL], ESKD, and death due to observed during the trial limited the vitedtoparticipateinADVANCE-ON, renal disease) because levels of serum strength of the conclusions. In addition, and 172 of 215 sites (80%) agreed. After creatinine and urinary albumin were the safety of intensive glucose control approval by the local ethics review only measured in a subgroup of patients in the presence of CKD has been ques- boards of each participating site, all sur- during post-trial follow-up. Outcomes tioned, with the Action to Control Car- viving trial patients at those sites were occurring during post-trial follow-up diovascular Risk in Diabetes (ACCORD) invited to enter post-trial follow-up. In were as reported by the study centers us- trial (11) recently reporting that its inten- January 2010, annual post-trial visits ing the standardized definitions used dur- sive glucose-lowering strategy increased commenced. At the first post-trial visit, ing the trial, without central adjudication. the risk of cardiovascular and all-cause informed consent was obtained and a death among participants with CKD standardized questionnaire completed Statistical Methods but not in those with normal kidney on the occurrence of all study outcomes Analyses were conducted according to function. of interest and all medications taken. A the initial treatment assignment. Treat- The outcomes of the 6-year post-trial random subset of 2,000 patients, bal- ment effects were examined using follow-up of the ADVANCE trial cohort, also anced across regions and across the cumulative incidence survival curves known as the ADVANCE-ObservatioNal prior randomized treatment arms, was and Cox proportional hazards models. (ADVANCE-ON) study, were recently pub- also invited to undergo assessment of Patients were censored at the first rele- lished (12). Here, we report on further HbA1c,fastingbloodglucose,blood vant end point: the date of death, date analyses that examine the long-term pressure, weight, serum creatinine, of last visit (for those still alive), or date effects of the intensive glucose control and urinary albumin-to-creatinine ratio last known to be alive for those whose 696 Long-term Benefits of Glucose Control on ESKD Diabetes Care Volume 39, May 2016

vital status was unknown at the end of gliclazide modified release), metformin, In patients at trial baseline with SBP levels the study (28 February 2014). Hazard glitazones, and a-glucosidase inhibitors ,140 mmHg, the risk reduction in ESKD ratios (HRs) were estimated for the in- but more use of insulin and other glu- was greater than in those with SBP levels trial period and over the entire period of cose-lowering therapies (including glip- .140 mmHg (HR 0.19 [95% CI 0.06, 0.55] follow-up. An additional post hoc obser- tins and glucagon-like peptide 1 analogs) vs. HR 0.77 [95% CI 0.46, 1.30], respectively, vational analysis was performed for the in both the intensive and standard Pheterogeneity = 0.01) (Fig. 2). post-trial period alone. Serial HRs with glucose control groups, irrespective of The nonsignificant effect on the risk 95% CIs were estimated at the end CKD stage (Supplementary Tables 1–3). of death due to renal disease observed of each calendar year of post-trial fol- The use of blood pressure–lowering during the in-trial period (HR 0.85 [95% low-up. The homogeneity of treatment agents, statins, and antiplatelet agents CI 0.45, 1.62]) remained similar after a effects for prespecified subgroups was was also comparable across the groups, ir- total of 9.9 years of follow-up (HR 0.89 tested by adding an interaction term to respective of the CKD stage (Supplementary [95% CI 0.60, 1.31]) (Fig. 1). the relevant Cox models. Tables 1–3). The Chronic Kidney Disease–Epidemi- Absolute Renal Effects Across the entire population over 9.9 ology Collaboration (CKD-EPI) equation Glycemic Control years, 194 participants would need to wasusedtocalculatetheestimated ThemeandifferenceinHbA (0.67% 1c be treated with intensive glucose con- glomerular filtration rate (eGFR). For [95% CI 0.64, 0.70], P , 0.001) observed trol to prevent one ESKD event (Table analyses by baseline CKD status, partic- at the end of randomized therapy was 1). Further, the number that would ipants were divided into those with CKD lost when measured on average 2.9 need to be treated (NNT) by CKD stage stage 1 (eGFR $90 mL/min/1.73 m2 years later at the first post-trial visit was 109 for CKD stages 1 and 2 and and urinary albumin-to-creatinine ratio (0.08% [95% CI 20.07, 0.22], P =0.29). 393 for CKD stage 3 or greater. The $30 mg/mg), CKD stage 2 (eGFR be- TherewasariseinHbA in the intensive 1c NNT by SBP was 120 for baseline SBP tween 60 and 89 mL/min/1.73 m2 and control group approaching that ob- ,140 mmHg and 368 for baseline SBP urinary albumin-to-creatinine ratio served in the standard control group. $140 mmHg (Table 1). $30 mg/mg), and CKD stage $3(eGFR The HbA1c levels of the two groups con- 2 ,60 mL/min/1.73 m with or without verged at the first post-trial visit (7.3% Other Outcomes albuminuria and those without CKD (eGFR vs. 7.3%, P =0.29)andremainedsimilar The rate of major hypoglycemia was low $60 mL/min/1.73 m2 and urinary albumin- at the last post-trial visit (12). overall, and the increase in risk for the to-creatinine ratio ,30 mg/mg) (15). intensive versus the standard glucose Theanalyseswereperformedwith ESKD or Renal Death control group observed during the trial SAS (version 9.2). All tests were two- During the in-trial period, 27 patients was no longer evident after post-trial sided, and P values ,0.05 were consid- recorded ESKD events and 37 patients follow-up (Supplementary Fig. 2). The ered to indicate statistical significance. died due to renal causes. During the absolute risk of hypoglycemia tended The protocol prespecified that no post-trial period, an additional 55 pa- to be slightly higher for the group with adjustments would be made for the tients recorded ESKD events and 64 pa- CKD stage 3 or greater compared with multiple statistical testing (12). In light tients died due to renal causes (Table 1). no CKD or CKD stage 1 and 2 irrespective of this, the findings were interpreted The significant reduction in the risk of of the original randomized groups. How- with the appropriate degree of caution. ESKD observed with intensive glucose ever, the increase in risk for the inten- control during the in-trial period (7 vs. sive versus standard glucose control RESULTS 20 events, HR 0.35 [95% CI 0.15, 0.83], groups was similarly no longer evident Of 10,082 patients originally assigned to P = 0.02) persisted after a total of 9.9 for subgroups of patients defined by the randomized treatments and alive at years of follow-up (29 vs. 53, HR 0.54 CKD stage after post-trial follow-up , the end of the trial, 8,494 (4,283 vs. 4,211 [95% CI 0.34, 0.85], P 0.01) (Fig. 1). (overall study period Pheterogeneity = for intensive vs. standard glucose control, Subgroup analyses examining the ef- 0.92). respectively) entered post-trial follow-up fects of intensive glucose control by pa- Intensive glucose control had no clear and 5,131 (2,638 vs. 2,493) of those still tient characteristics at trial baseline effects on overall all-cause mortality, alive completed a visit during the final suggested no heterogeneity with similar cardiovascular death, major cardiovas- year of the study (12). The median in-trial, risk reductions for males and females, cular events, myocardial infarction, or post-trial, and total follow-up periods those aged above and below 65 years, stroke. In addition, there was no evi- were 5.0 years, 5.4 years, and 9.9 years, and those with HbA1c levels above and dence that baseline CKD status had any respectively (Supplementary Fig. 1). As below the median (7.2%) (Fig. 2). impact on the effect of intensive previously reported, the prerandomiza- In contrast, heterogeneity was ob- glucose control on these outcomes tion characteristics of the original glu- served for patients according to CKD (Fig. 3) (all Pheterogeneity . 0.2) during cose control trial population and of the stage, as well as patients with systolic the in-trial period or during extended follow-up study cohort were similar (16). blood pressure (SBP) levels below follow-up. or above 140 mmHg (Fig. 2, both P , Use of Glucose-Lowering and Other 0.05). A graded reduction in the CONCLUSIONS Therapies strength of the effect of intensive glu- After following the ADVANCE trial co- During post-trial follow-up, there was cose control on ESKD was seen as CKD hort for a total of 9.9 years, we show less use of sulfonylureas (including stage increased (Fig. 2) (Pheterogeneity =0.04). that a prior period of intensive glucose care.diabetesjournals.org Wong and Associates 697

Table 1—Comparison of NNT over 5 years and 9.9 years to prevent one ESKD event overall 5-Year follow-up period 9.9-Year follow-up period Annual event rate Annual event rate NNT to prevent NNT to prevent Population and Participants, Standard, Intensive, one ESKD event Participants, Standard, Intensive, one ESKD over subgroup N (%) % % over 5 years N (%) % % 9.9 years 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 in standard 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-creatinine ratio $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 $3wasdefined as eGFR ,60 mL/min/1.73 m2 with or without albuminuria. Mild CKD included patients with stages 1 and 2 and moderate CKD included patients with stage 3 CKD. eGFR is calculated using the EPI-CKD formula.

control continues to protect against the baseline (SBP ,140 mmHg). Impor- include the Epidemiology of Diabetes In- development of ESKD in patients with tantly, the impact of intensive glucose terventions and Complications (EDIC) type 2 diabetes. The patients who ap- control on mortality or major cardiovas- study in a population of younger individ- pear to benefit the most are those cular events was not adversely affected uals with type 1 diabetes, which reported with preserved kidney function, with in- by CKD at baseline during either the trial that a prior period of intensive glucose termediate effects in the group with or overall study follow-up. control reduced the long-term risk of CKD stage 1 or 2 and lesser effects in Our data provide the strongest evi- developing renal impairment (eGFR ,60 participants with CKD stage 3 or greater dence to date regarding the renal bene- mL/min/1.73 m2) by 50% after a median at baseline. Greater reductions in ESKD fits of intensive glucose lowering and follow-up of 22 years (17). However, in were also observed in participants are consistent with data on intermedi- that study a clear benefit for ESKD was with better blood pressure control at ate outcomes from other studies. These not demonstrated, most likely because

Figure 1—Summary plot showing the effects of intensive glucose lowering compared with standard glucose lowering on ESKD and/or death due to renal cause during the in-trial, post-trial, and overall study periods of follow-up. Renal death, death due to renal causes. 698 Long-term Benefits of Glucose Control on ESKD Diabetes Care Volume 39, May 2016

Figure 2—Subgroup analyses by baseline characteristics for the outcome of ESKD. The P value provided represents test for heterogeneity between subgroups. ARB, angiotensin receptor blocker; BP, blood pressure. care.diabetesjournals.org Wong and Associates 699

Figure 3—Forest plots of all-cause mortality and major cardiovascular events by randomized subgroups for the in-trial period (A) and overall study period (B). The P value provided represents a test for heterogeneity between subgroups. MI, myocardial infarction. few ESKD events were recorded. Simi- As the development of ESKD often takes term, suggesting the earlier period of larly the long-term follow-up of the decades to appear after the onset of di- intensive glucose control may have pre- UKPDS cohort of patients newly diag- abetes, it might well be anticipated that vented structural changes in both the nosed with type 2 diabetes reported slowing of this process would take years glomeruli and tubulointerstitium, when persistent microvascular (eye and renal to become evident, especially if it re- renal function was relatively intact. events) and emerging macrovascular quires abrogation of diabetes-induced Similar differences were found in sub- benefits in those previously assigned to structural changes in the glomerulus groups defined by baseline blood pres- intensive glucose lowering, with bene- (19,20). In contrast, the effects of sure, with a much greater reduction in fits for defined by lower renin-angiotensin-aldosterone system ESKD by the end of overall follow-up in risk of increases in serum creatinine blockade and blood pressure lowering participants with SBP at baseline below to .250 mmol/L. The ACCORD study are likely to have a more rapid onset the hypertensive range (,140 mmHg). reported a numerically lower risk of re- and offset in response to treatment. These findings also support the premise nal failure with intensive glucose lower- Our results highlight the importance that greater benefits will be obtained ing; however, this did not achieve of commencing intensive glucose con- through intensive glucose control ear- statistical significance (18). The results trol before diabetic kidney disease de- lier in the life course of the patient regardingtheeffectsonESKDinthe velops, as lesser renal benefitwas with type 2 diabetes. While a recent re- long-term follow-up of the ACCORD trial observed in participants with an estab- port has raised concerns regarding a are awaited with interest. lished reduction in kidney function, sug- possible increase in the risk of adverse InADVANCE,thedifferenceinthe gesting that the relative contribution of outcomes in the presence of CKD with rate of ESKD events between the inten- glucose-dependent and glucose-inde- intensive glucose control, particularly sive and the standard glucose control pendent pathways may vary at different risk of death (11), we found no evidence groups took .2 years to emerge but levels of kidney function. The lesser ben- for this. Collectively, these data support then persisted (with a further numeri- efit in those with moderately reduced early intensive glucose control and optimal cally lower number of events) to the kidney function (CKD stage 3 or greater) blood pressure levels for the prevention of end of the overall study period, even may indicate that glucose-independent long-term renal complications in individu- after the HbA1c converged. The risk mechanisms of renal progression are als with type 2 diabetes. reduction for ESKD events observed in predominant in the later stages of the An interesting finding was the lack of ADVANCE-ON likely goes beyond a sim- disease (21). In the subgroup of patients consistency in the results for ESKD and ple carry forward of the effects ob- without baseline CKD, the benefits for renal death. A low number of events is served during the original trial period. ESKD were maintained in the long one reason. Death purely attributed to 700 Long-term Benefits of Glucose Control on ESKD Diabetes Care Volume 39, May 2016

renal causes is less common than death for scientific lectures from AstraZeneca. V.P. 8. Nathan DM, Cleary PA, Backlund JY, et al.; due to cardiovascular or cerebrovascu- reports honoraria for scientific lectures from Diabetes Control and Complications Trial/ lar causes. However, establishing cause Boehringer Ingelheim, Merck, AbbVie, Roche, Epidemiology of Diabetes Interventions and AstraZeneca, and Servier and serves on steering Complications (DCCT/EDIC) Study Research of death during any clinical trial may be committees and/or advisory boards supported Group. Intensive diabetes treatment and car- challenging. During the ADVANCE trial, by AbbVie, Astellas, Baxter, Boehringer Ingelheim, diovascular disease in patients with type 1 di- renal death was adjudicated, whereas Bristol-Myers Squibb, GlaxoSmithKline, Janssen, abetes. N Engl J Med 2005;353:2643–2653 during the ADVANCE-ON post-trial fol- and Pfizer. J.C. reports research grants adminis- 9. The Diabetes Control and Complications Trial tered through the University of Sydney for the Research Group. The effect of intensive treat- low-up renal death could not be adjudi- ADVANCE trial and the ADVANCE-ON post- fi ment of diabetes on the development and cated. In addition, it may be dif cult to trial study and honoraria from Servier for progression of long-term complications in in- ascertain whether a death is due to pro- speaking about these studies at scientificmeet- sulin-dependent diabetes mellitus. N Engl gressive kidney failure, intercurrent car- ings. P.H. is a member of College` International J Med 1993;329:977–986 diovascular event, or some combination de Recherche Servier. B.W. has received hono- 10. Perkovic V, Heerspink HL, Chalmers J, et al.; raria from Servierfor lectures atscientificmeet- of the two. This could result in greater ADVANCE Collaborative Group. Intensive glucose ings. S.Z. reports past participation in advisory control improves kidney outcomes in patients uncertainty as to the effects on this out- boards and/or receiving honoraria from Amgen with type 2 diabetes. Kidney Int 2013;83:517–523 come compared with that of ESKD, which Australia, AstraZeneca/Bristol-Myers Squibb 11. Papademetriou V, Lovato L, Doumas M, is simpler to define as requirement for Australia, Janssen-Cilag, Merck Sharp & Dohme et al.; ACCORD Study Group. Chronic kidney dis- fi (Australia), Novartis Australia, Sano , Servier ease and intensive glycemic control increase dialysis or renal transplantation. Indeed, Laboratories, and Takeda Australia as well as other clinical trials such as Reduction of cardiovascular risk in patients with type 2 dia- Monash University undertaking contract work betes. Kidney Int 2015;87:649–659 Endpoints in NIDDM with the Angiotensin for AstraZeneca Pty Ltd./Bristol-Myers Squibb 12. Zoungas S, Chalmers J, Neal B, et al.; fl II Antagonist Losartan (RENAAL) and the Australia Pty Ltd. No other potential con icts ADVANCE-ON Collaborative Group. Follow-up of interest relevant to this article were reported. Irbesartan Trial of blood-pressure lowering and glucose control M.G.W. wrote the first Author Contributions. in type 2 diabetes. N Engl J Med 2014;371:1392– (IDNT) have similarly not been able to draft of the manuscript. V.P., J.C., M.W., and S.Z. 1406 identify beneficial effects regarding re- conceived the study protocol and analysis plan, 13. Patel A, MacMahon S, Chalmers J, et al.; researched data, and reviewed and edited nal death (4,5). It was also not possible ADVANCE Collaborative Group. Effects of a fixed the manuscript. Q.L. completed all statistical anal- to report progression or regression of combination of perindopril and indapamide on ysis. M.E.C., P.H., S.Ha., S.He., S.M., G.M., M.M., macrovascular and microvascular outcomes albuminuria or doubling of serum creat- D.M., B.N., N.P., A.R., and B.W. contributed to inine as occurred in the original trial be- discussion and reviewed and edited the manuscript. in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. cause serum creatinine levels and Prior Presentation. Parts of this study were – presented in abstract form at the International Lancet 2007;370:829 840 urinary albumin-to-creatinine ratios at 14. Patel A, MacMahon S, Chalmers J, et al.; the first post-trial visit were only avail- Diabetes Federation 23rd World Diabetes Con- gress, Vancouver, BC, Canada, 30 November–4 ADVANCE Collaborative Group. Intensive blood able and able to be collected for a subset December 2015. glucose control and vascular outcomes in pa- of participants (13). tients with type 2 diabetes. N Engl J Med 2008; – A clear strength of this study is the long- References 358:2560 2572 15. KDIGO. Clinical Practice Guideline for the term follow-up of a large and diverse pa- 1. U.S. Renal Data System. USRDS 2014 Annual Evaluation and Management of Chronic Kidney tient population with type 2 diabetes. The Data Report: Cost of End-stage Renal Disease in Disease. Kidney Int 2013;3(Suppl.):63–72 limitations include nonadjudicated renal the United States. Bethesda, MD, National Insti- 16. Zoungas S, Woodward M, Li Q, et al.; tutes of Health, National Insitute of Diabetes ADVANCE Collaborative group. Impact of age, end points and the lack of complete bio- and Digestive and Kidney Diseases, 2014 age at diagnosis and duration of diabetes on chemical data for all participants during 2. Liyanage T, Ninomiya T, Jha V, et al. World- the risk of macrovascular and microvascular the post-trial follow-up. 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M.G.W. reports fees 2008;359:1577–1589 2000;9:323–331