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

Abstract

BackgroundWe 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 ResultsWe 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.ConclusionsOf 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.

Diabetic Cardiomyopathy: Current Approach and Potential Diagnostic and Therapeutic Targets

“…As for biomarkers evaluating the risk for cardiovascular events in diabetic patients, MMP3, osteopontin and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and their combined value score are currently proposed to be introduced in evaluating diabetic patients, but first there is a need for more clear evidence that their use offers a more accurate risk stratification than the traditional risk factors [14]. …”

“…Various metabolic changes are comprised during long time evolving DM: the cardiac uptake of albumin-fatty acid is augmented; the storage and catabolism of endogenous triglycerides are increased, as well as the circulating lipoprotein levels, as a consequence of enhanced hepatic VLDL synthesis [14]. In DCM, calcium signaling is altered; hence the contraction-relaxation dynamic is affected, with consequent alteration of structural components and activation of various signaling pathways, including NF-kB, c-Jun N-terminal kinases, and p38 mitogen-activated protein kinases through oxidative modifications.…”

Polymorphism rs2073618 of the osteoprotegerin gene as a potential marker of subclinical carotid atherosclerosis in Caucasians with type 2 diabetes mellitus

“…In the Second Manifestations of the ARTerial disease (SMART) study, 23 novel biomarkers were evaluated for their potential to enhance predictive performance in patients with type 2 diabetes [19]. Mainly, their research was focused on other bone-related proteins (osteocalcin, osteonectin, and osteopontin), and not on OPG.…”

Biomarkers for cardiovascular risk in patients with diabetes: Table 1

“…Recent clinical studies have shown that both NT-proBNP and hs-troponin T/I could be posed predictive biomarkers in patient population with established CV disease, at higher risk of myocardial dysfunction beyond traditional CV or metabolic risk factors and DM. 5 However, the role of natriuretic peptides and cardiac troponins in subjects with pre-diabetes and also individuals with DM without established CV disease is uncertain. All these findings indicate in particular that traditional practical biomarker tools for the assessment of CV and metabolic risk in subjects with pre-diabetes, overweightobese individuals and patients with known type-1 and type-2 DM should be reappraised and novel biological markers of advanced atherosclerosis may be incorporated into risk scores.…”