Prognostic Implications of Biomarker Assessments in Patients With Type 2 Diabetes at High Cardiovascular Risk: A Secondary Analysis of a Randomized Clinical Trial.
OBJECTIVE
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.


METHODS
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.


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


METHODS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT01107886.
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Benjamin M
BM
Scirica
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Deepak L
DL
Bhatt
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Eugene
E
Braunwald
Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Itamar
I
Raz
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Matthew A
MA
Cavender
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
KyungAh
K
Im
Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Ofri
O
Mosenzon
Women's College Research Institute and Cardiovascular Division, Department of Medicine, Women's College Hospital, Toronto, Ontario, Canada4Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Jacob A
JA
Udell
AstraZeneca Research and Development, Gaithersburg, Maryland.
Boaz
B
Hirshberg
AstraZeneca Research and Development, Gaithersburg, Maryland.
Pia S
PS
Pollack
National Heart and Lung Institute, Imperial College, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, London, England7INSERM U-1148, Département Hospitalo-Universitaire FIRE (Fibrosis-Inflammation-Remodelling), Université Paris-Diderot, Paris, France8Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.
Ph Gabriel
PG
Steg
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Petr
P
Jarolim
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
David A
DA
Morrow