Implications of Biomarker Assessments in Type 2 Diabetes
What is the incremental prognostic value of biomarkers that reflect different pathophysiologic processes in patients with type 2 diabetes?
SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) was a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety of saxagliptin versus placebo in 16,492 outpatients with type 2 diabetes with overt cardiovascular disease (CVD) or multiple risk factors. In this secondary analysis, widely used biomarkers were evaluated to ascertain whether they would provide incremental prognostic value in the risk stratification. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). Patients were randomized to saxagliptin versus placebo in addition to standard care. Concentrations of high-sensitivity troponin T (hs-TnT), N-terminal pro–B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP) were analyzed continuously and by established cut points. CV death, MI, ischemic stroke, and hospitalization for heart failure (HF) were adjudicated by a blinded events committee.
Of the 16,492 patients, 5,455 (33.1%) were female and 11,037 (66.9%) were male. Mean (standard deviation) age was 65.0 (8.5) years (range, 39-99 years). Baseline biomarkers were measured in 12,310 patients. Elevated levels of each biomarker were associated significantly with increased risk for all CV endpoints. When added to clinical variables, biomarkers significantly improved the discrimination and appropriate reclassification of risk. Elevated hs-TnT was associated with an increased risk of CV death (adjusted hazard ratio [AHR], 3.07; 95% confidence interval [CI], 2.35-4.02; p < 0.001), MI (AHR, 2.13; 95% CI, 1.69-2.67; p < 0.001), and hospitalization for HF (AHR, 3.85; 95% CI, 2.82-5.27; p < 0.001). Elevated NT-proBNP was also associated with an increased risk of CV death (AHR, 3.09; 95% CI, 2.46-3.89; p < 0.001), MI (AHR, 1.95; 95% CI, 1.51-2.53; p < 0.001), and hospitalization for HF (AHR, 3.92; 95% CI, 3.11-4.92; p < 0.001). Elevated hs-CRP was more weakly associated with an increased risk of CV death (AHR, 1.49; 95% CI, 1.22-1.82; p < 0.001) and hospitalization for HF (AHR, 1.47; 95% CI, 1.20-1.81; p < 0.001). Consistent results were seen in patients with or without established CVD.
The authors concluded that strategies to improve risk stratification in patients with type 2 diabetes, with or without CVD, should consider incorporation of biomarker data into standard risk algorithms.
This secondary analysis of a randomized clinical trial of patients with type 2 diabetes with overt CVD or multiple risk factors, reports that elevated levels of hs-TnT, NT-proBNP, and hs-CRP significantly improved the discrimination and appropriate reclassification of CV risk, particularly hs-TnT and NT-proBNP levels. It appears that biomarkers may appropriately risk stratify patients with diabetes in terms of future CV events, and challenge the traditional differentiation between primary and secondary prevention based on clinical history alone. If prospectively validated, we should consider incorporating biomarker data into standard risk algorithms to provide more accurate risk stratification than clinical variables alone.
Keywords: Biological Markers, Cardiovascular Diseases, C-Reactive Protein, Diabetes Mellitus, Type 2, Heart Failure, Metabolic Syndrome X, Myocardial Infarction, Natriuretic Peptide, Brain, Peptide Fragments, Primary Prevention, Risk Factors, Stroke, Troponin T
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