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Long-Term Benefits of Intensive Glucose Control for Preventing End-Stage Kidney Disease: ADVANCE-ON

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Long-Term Benefits of Intensive Glucose Control for Preventing End-Stage Kidney Disease: ADVANCE-ON 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 Kidney 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 Epidemiology, Johns Hopkins University, Baltimore, MD vents end-stage kidney disease (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, Clinical trial 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
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