title: Relationship between levels of advanced glycation end products and their soluble receptor and adverse outcomes in adults with type 2 diabetes.
abstract: OBJECTIVE
  This study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications.
  
  
  METHODS
  A case-cohort study was performed in 3,763 participants with prevalent diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The hazard ratios (HRs) for death, major cardiovascular events, and new or worsening nephropathy were derived using Cox regression models, and the ability of sRAGE and AGE levels to reclassify the risk of nephropathy was assessed.
  
  
  RESULTS
  After adjustment for a range of possible confounders and other risk factors, sRAGE levels were associated with all-cause mortality (HR 1.11 for a 1-SD increase of log sRAGE [95% CI 1.00-1.22]; P = 0.045) and new or worsening nephropathy (HR 1.20 for a 1-SD increase of log sRAGE [95% CI 1.02-1.41]; P = 0.032). Circulating AGE levels were also independently associated with new or worsening nephropathy (HR 1.21 for a 1-SD increase [95% CI 1.08-1.36]; P = 0.001). Both markers also significantly improved the accuracy with which the 5-year risk of new or worsening nephropathy could be predicted (net reclassification index in continuous model, 0.25 for sRAGE and 0.24 for AGE levels).
  
  
  CONCLUSIONS
  In adults with type 2 diabetes, increased levels of sRAGE are independently associated with new or worsening kidney disease and mortality over the next 5 years. Higher levels of AGE are also associated with an increased risk of adverse renal outcomes. The AGE/RAGE axis may be of importance in the prevention and management of diabetes complications.
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, U.K. Department of Epidemiology, Johns Hopkins University, Baltimore, MD markw@georgeinstitute.org.au.
authors.forename: Mark
authors.initials: M
authors.lastname: Woodward
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Neal
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Raelene
authors.initials: R
authors.lastname: Pickering
authors.affiliation: Hôpital Bichat-Claude Bernard and Université Paris 7, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.affiliation: University College London and the National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, U.K.
authors.forename: Bryan
authors.initials: B
authors.lastname: Williams
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Sophia
authors.initials: S
authors.lastname: Zoungas
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Chalmers
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Hillis
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000517:prevention & control; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000517:prevention & control; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000517:prevention & control; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004812:Epidemiologic Methods; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008297:Male; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D011971:Receptors, Immunologic; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic