title: Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus.
abstract: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors.
  
  
  
  We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C-reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c-statistic and net reclassification index (NRI; continuous and based on 10-year risk strata 0-10%, 10-20%, 20-30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N-terminal prohormone of B-type natriuretic peptide, osteopontin, and MMP-3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c-statistic with 0.03 (95% CI 0.01-0.05), and the continuous NRI was 0.37 (95% CI 0.21-0.52). In EPIC-NL, the multimarker model increased the c-statistic with 0.03 (95% CI 0.00-0.03), and the continuous NRI was 0.44 (95% CI 0.23-0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03-0.21) in SMART and 0.07 (95% CI -0.04-0.17) in EPIC-NL.
  
  
  
  Of the 23 evaluated biomarkers from different pathophysiological pathways, N-terminal prohormone of B-type natriuretic peptide, osteopontin, MMP-3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited.
authors.affiliation: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: van der Leeuw
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joline W J
authors.initials: JW
authors.lastname: Beulens
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: van Dieren
authors.affiliation: CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Department of Genetics and Cell Biology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Jan F C
authors.initials: JF
authors.lastname: Glatz
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: W M Monique
authors.initials: WM
authors.lastname: Verschuren
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: van der Graaf
authors.affiliation: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Frank L J
authors.initials: FL
authors.lastname: Visseren
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Peelen
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands y.t.vanderschouw@umcutrecht.nl.
authors.forename: Yvonne T
authors.initials: YT
authors.lastname: van der Schouw
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000517:prevention & control*; D003925:Diabetic Angiopathies / Q000097:blood / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009426:Netherlands; D053495:Osteopontin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D053495:Osteopontin; D020097:Natriuretic Peptide, Brain; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
keywords: biomarker; cardiovascular disease prevention; cardiovascular disease risk factors; risk stratification