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Original Investigation
December 2016

Prognostic Implications of Biomarker Assessments in Patients With Type 2 Diabetes at High Cardiovascular RiskA Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
  • 3Women’s College Research Institute and Cardiovascular Division, Department of Medicine, Women’s College Hospital, Toronto, Ontario, Canada
  • 4Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
  • 5AstraZeneca Research and Development, Gaithersburg, Maryland
  • 6National Heart and Lung Institute, Imperial College, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, London, England
  • 7INSERM U-1148, Département Hospitalo-Universitaire FIRE (Fibrosis-Inflammation-Remodelling), Université Paris-Diderot, Paris, France
  • 8Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 9Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA Cardiol. 2016;1(9):989-998. doi:10.1001/jamacardio.2016.3030
Key Points

Question  Do cardiac biomarkers provide incremental prognostic value in patients with type 2 diabetes?

Findings  In this secondary analysis of a randomized clinical trial of 12 310 patients with overt cardiovascular disease or multiple risk factors, elevated levels of high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, and high-sensitivity C-reactive protein significantly improved the discrimination and appropriate reclassification of risk, in particular for high-sensitivity troponin T and N-terminal pro–B-type natriuretic peptide.

Meaning  Biomarkers appropriately risk stratify patients with diabetes in terms of future cardiovascular events and challenge the traditional differentiation between primary and secondary prevention based simply on clinical history.

Abstract

Importance  Cardiac biomarkers provide insights into pathophysiologic processes and offer an attractive strategy for the assessment of cardiovascular risk.

Objective  To assess the incremental prognostic value of biomarkers that reflect different pathophysiologic processes in patients with type 2 diabetes.

Design, Setting, and Participants  The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 is a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety of saxagliptin vs 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). The study was performed from May 10, 2010, to June 15, 2013.

Interventions  Randomization to saxagliptin vs placebo in addition to standard care.

Main Outcomes and Measures  Concentrations of high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, and high-sensitivity C-reactive protein were analyzed continuously and by established cut points. Cardiovascular death, myocardial infarction, ischemic stroke, and hospitalization for heart failure (HF) were adjudicated by a blinded events committee.

Results  Of the 16 492 patients, 5455 (33.1%) were female and 11 037 (66.9%) were male. Mean (SD) 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 cardiovascular end points. When added to clinical variables, biomarkers significantly improved the discrimination and appropriate reclassification of risk. Elevated high-sensitivity troponin T was associated with an increased risk of cardiovascular death (adjusted hazard ratio [AHR], 3.07; 95% CI, 2.35-4.02; P < .001), myocardial infarction (AHR, 2.13; 95% CI, 1.69-2.67; P < .001), and hospitalization for HF (AHR, 3.85; 95% CI, 2.82-5.27; P < .001). Elevated N-terminal pro–B-type natriuretic peptide was also associated with an increased risk of cardiovascular death (AHR, 3.09; 95% CI, 2.46-3.89; P < .001), myocardial infarction (AHR, 1.95; 95% CI, 1.51-2.53; P < .001), and hospitalization for HF (AHR, 3.92; 95% CI, 3.11-4.92; P < .001). Elevated high-sensitivity C-reactive protein was more weakly associated with an increased risk of cardiovascular death (AHR, 1.49; 95% CI, 1.22-1.82; P < .001) and hospitalization for HF (AHR, 1.47; 95% CI, 1.20-1.81; P < .001). Consistent results were seen in patients with or without established CVD.

Conclusions and Relevance  A substantial proportion of patients with stable type 2 diabetes with established CVD or multiple clinical risk factors have evidence of ongoing myocardial injury, hemodynamic stress, or systemic inflammation. Biomarker risk stratification thus challenges the traditional differentiation between primary and secondary prevention based simply on clinical history. 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.

Trial Registration  clinicaltrials.gov Identifier: NCT01107886

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