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Management of Patients with Diabetes and CKD:&Nbsp www.kidney-international.org meeting report Management of patients with diabetes and CKD: conclusions from a “Kidney Disease: OPEN Improving Global Outcomes” (KDIGO) Controversies Conference Vlado Perkovic1,2, Rajiv Agarwal3, Paola Fioretto6, Brenda R. Hemmelgarn7,8,9,10, Adeera Levin11,12,13, Merlin C. Thomas4,5, Christoph Wanner14, Bertram L. Kasiske15, David C. Wheeler16 and Per-Henrik Groop4,17,18,19; for Conference Participants20 1George Institute for Global Health, University of Sydney, Sydney, NSW, Australia; 2Royal North Shore Hospital, Sydney, New South Wales, Australia; 3Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA; 4Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; 5Department of Medicine, Monash University, Melbourne, Victoria, Australia; 6Department of Medicine, University of Padova, Italy; 7Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 8Interdisciplinary Chronic Disease Collaboration, Calgary, Alberta, Canada; 9Libin Cardiovascular Institute and Institute of Public Health, University of Calgary, Calgary, Alberta, Canada; 10Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; 11Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada; 12BC Provincial Renal Agency, Vancouver, British Columbia, Canada; 13Centre for Health Evaluation and Outcomes Research, St. Paul’s Hospital, Vancouver, British Columbia, Canada; 14Renal Division, University Hospital of Würzburg, Würzburg, Germany; 15Division of Nephrology, Hennepin County Medical Center, Minneapolis, Minnesota, USA; 16University College London, London, UK; 17Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; 18Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; and 19Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland The prevalence of diabetes around the world has reached Copyright ª 2016, International Society of Nephrology. Published by epidemic proportions and is projected to increase to 642 Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The he prevalence of diabetes around the world is expected presence of kidney disease is associated with a markedly to reach 642 million people by 2040.1 About 40% of elevated risk of cardiovascular disease and death in people T people with diabetes will develop chronic kidney dis- with diabetes. Several new therapies and novel ease (CKD),2 including a significant number who will develop investigational agents targeting chronic kidney disease end-stage kidney disease (ESKD). patients with diabetes are now under development. This Diabetes is the leading cause of ESKD in most developed conference was convened to assess our current state of countries, and has driven growth in ESKD globally over – knowledge regarding optimal glycemic control, current recent decades.3 5 There is a strong economic and health antidiabetic agents and their safety, and new therapies imperative to improve outcomes for people with diabetes and being developed to improve kidney function and kidney disease. cardiovascular outcomes for this vulnerable population. The identification of renin-angiotensin system (RAS) Kidney International (2016) 90, 1175–1183; http://dx.doi.org/10.1016/ blockade as an effective strategy for the prevention of – j.kint.2016.09.010 ESKD in diabetes was a major step forward,6 8 but subse- KEYWORDS: antidiabetic agents; cardiovascular disease; chronic kidney quent research has had limited success in building upon disease; diabetes; glycemic control; renoprotection these gains. A number of promising treatments have been found to be ineffective or harmful, many of which have – now been abandoned in this population.9 14 One common Correspondence: Vlado Perkovic, The George Institute for Global Health, 321 Kent Street, Sydney NSW 2000, Australia. E-mail: [email protected]; feature of these failures has been the emergence of unex- or Per-Henrik Groop, Abdominal Center Nephrology, University of Helsinki pected adverse effects, highlighting the importance of safety and Helsinki University Hospital Biomedicum Helsinki, Haartmaninkatu 8, 00290 monitoring in future trials and review of what is known Helsinki, Finland. E-mail: per-henrik.groop@helsinki.fi about the safety of existing treatments in this patient 20See Appendix for list of other conference participants. population. Received 5 August 2016; revised 16 September 2016; accepted 22 With a number of new agents under development tar- September 2016 geting newly identified mechanistic pathways underlying Kidney International (2016) 90, 1175–1183 1175 meeting report V Perkovic et al.: Management of diabetes and CKD: a KDIGO conference report diabetic kidney disease (DKD), it is timely to reflect on what Additional opportunities to further define the link has been learned in order to better optimize both the care of between glycemic control and kidney disease may be affected patients as well as provide a road map for future provided by ongoing studies including the follow-up of research. Kidney Disease: Improving Global Outcomes the TODAY trial, which focused on youth and adolescents (KDIGO) convened a Controversies Conference in Van- with early onset T2DM who have a higher incidence of couver in February 2015 to bring together a multidisci- kidney disease.34 Furthermore, ongoing follow-up of plinary group of key experts from around the world to participants in several diabetes intervention and preven- explore these issues. This report summarizes the key out- tion studies of more than 10 years duration should pro- comesofthisconference. vide additional data on the impact of glycemic control on various complications of diabetes, including kidney Lifestyle measures, including diet and exercise in DKD disease.35,36 Salt intake, obesity, and sedentary living have been Glucose-lowering agents. The availability of a growing linked to morbidity and mortality in multiple epidemio- range of medications to manage T2DM has highlighted logical studies.15 Dietary sodium restriction has been knowledge gaps that still have not been resolved. Metfor- demonstrated to reduce blood pressure (BP) and albu- min is an important therapy that is underutilized in – minuria16 19 and enhances the effects of RAS inhibition. patients with CKD largely because of the risk of lactic However, optimal dietary sodium intake in DKD remains acidosis in this setting.37 It may be possible to use reduced controversial. doses of metformin (# 1 g per day) in patients with Other lifestyle interventions such as weight loss, and stable impaired renal function, with a plan to discontinue physical exercise, as well as supplementation with mono- and therapy and seek review in the event of significant inter- poly-unsaturated fats, have been shown to improve glycemic current illness.37 Although the safety of this strategy has control, lower BP, reduce albuminuria, and alter high-risk been questioned, many guidelines now suggest the use of biomarker profiles in the general population and are of in- metformin down to a glomerular filtration rate (GFR) of – – terest in individuals with diabetes and CKD.20 23 In the 30 ml/min/1.73 m2.38 41 recently completed Look AHEAD study, patients randomized Preclinical and post hoc clinical analyses from early trials to a multifactorial lifestyle approach, including dietary advice suggest that glucagon-like peptide 1 (GLP-1) receptor ago- and increased exercise, demonstrated slower progression of nists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium- CKD than patients in the comparator group who received glucose cotransporter 2 (SGLT2) inhibitors may afford renal support and education24 but the effects on cardiovascular protection, partly independent of their glycemic effects.42,43 (CV) events and mortality were disappointing. It is hoped Although most trials are designed to address CV safety in that there will be further follow-up of these patients to order to meet the requirements of regulatory agencies, there determine if the renal benefits based on lifestyle interventions are likely to be sufficient renal endpoints in some to deter- are sustained. mine whether these new approaches to lower glucose will confer renal benefits. Glycemic control SGLT2 inhibitors are of great interest, particularly due to The fundamental abnormality in diabetes is abnormal glucose the marked reduction in CV mortality and renal risk as re- metabolism, and the degree of abnormality predicts devel- ported from the EMPA-REG OUTCOME trial, and suggested – opment of nephropathy,25 but the role of intensive glycemic renoprotection from the CANTATA-SU trial.44 46 Of note, the control on kidney outcomes remains controversial. Trials of balance of risks and benefits in people with CKD will be intensive glucose control, such as the DCCT/EDIC trial in important to define separately, particularly as the glucose- type 1 diabetes mellitus (T1DM), were inadequately powered lowering effects decline as estimated glomerular filtration
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