Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus

Abstract

Background: 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.

Methods and results: 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.

Conclusions: 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.

Keywords: biomarker; cardiovascular disease prevention; cardiovascular disease risk factors; risk stratification.

Figure 1

Multivariable adjusted hazard ratios for risk of major cardiovascular events for the highest vs the lowest quartile of each biomarker in the Second Manifestions of ARTerial disease (SMART) study and European Prospective Investigation into Cancer and Nutrition‐NL (EPIC‐NL) study (adjusted for sex, age at diabetes mellitus diagnosis, duration of diabetes mellitus, Hb_A1c, systolic blood pressure, TC/HDL ratio, urinary albumin/creatinine ratio, smoking status and previous CVE. bFGF indicates basic fibroblast growth factor; CRP, C‐reactive protein; CVE, cardiovascular event; E‐FABP, epidermal‐type fatty acid binding protein; HbA1c, glycated hemoglobin; HDL, high‐density lipoprotein; H‐FABP, heart‐type fatty acid binding protein; MMP, matrix metalloproteinase; NT‐proBNP, N‐terminal prohormone of B‐type natriuretic peptide; PlGF, placental growth factor; SAA, serum amyloid A; sFLT, soluble FMS‐like tyrosine kinase; sICAM, soluble intercellular adhesion molecule; sVCAM, soluble vascular cell adhesion molecule; TIMP, tissue inhibitor of matrix metalloproteinase; VEGF, vascular endothelial growth.

Figure 2

Predicted risks with base model vs predicted risks with four biomarkers (NT‐proBNP, osteopontin, MMP‐3) added to the base model for patients without CVE events and for patients with CVE events who had available 10‐year follow‐up (n=551) from SMART. CVD indicates cardiovascular disease; CVE, cardiovascular event; MMP, matrix metalloproteinase; NT‐proBNP, N‐terminal prohormone of B‐type natriuretic peptide; SMART; Second Manifestions of ARTerial disease.