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Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia
Hertzel C Gerstein1, Guillaume Paré2, Matthew J McQueen2
1From Population Health Research Institute (H.C.G., G.P., M.J.M., S.F.L., J.P., S.Y.) and Thrombosis and Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences and McMaster University, Ontario, Canada; Sanofi Aventis Deutschland GmbH R&D Division Diabetes (H.H., S.H.), Frankfurt, Germany; and ANMCO Research Centre (A.P.M.), Florence, Italy. gerstein@mcmaster.ca.
Insights
This study identified key serum biomarkers that predict cardiovascular events and death in individuals with dysglycemia. These cardiometabolic biomarkers significantly improve risk prediction beyond clinical factors alone.
Area of Science:
- Cardiology
- Biomarker Discovery
- Metabolic Disease Research
Background:
- Cardiovascular (CV) outcomes are a major concern in individuals with dysglycemia.
- Serum biomarkers may offer a way to identify high-risk individuals.
- The Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial provided a cohort for this biomarker analysis.
Purpose of the Study:
- To identify novel serum biomarkers for predicting CV outcomes and death in people with dysglycemia.
- To assess if these biomarkers improve risk prediction when added to existing clinical measurements.
Main Methods:
- Multiplex analysis of 284 cardiometabolic biomarkers in serum samples from 8494 participants.
- Forward-selection Cox regression models were used to identify independent determinants of CV events and death.
- Biomarkers were evaluated for their ability to predict composite outcomes including myocardial infarction, stroke, CV death, heart failure hospitalization, revascularization, and all-cause death.
Main Results:
- Analysis included 8401 participants and 237 biomarkers.
- Ten biomarkers independently predicted composite CV outcomes when added to clinical variables.
- Fifteen biomarkers, including the CV predictors, independently predicted all-cause death.
- The addition of biomarkers improved the C-statistic for predicting death from 0.64 to 0.75.
Conclusions:
- A hypothesis-free approach successfully identified combinations of up to 15 cardiometabolic biomarkers.
- These biomarkers are independent determinants of CV outcomes or death in individuals with dysglycemia.
- The findings suggest potential for improved risk stratification in this population.
Background:
Serum biomarkers may identify people at risk for cardiovascular (CV) outcomes. Biobanked serum samples from 8494 participants with dysglycemia in the completed Outcome Reduction With Initial Glargine Intervention trial were assayed for 284 biomarkers to identify those that could identify people at risk for a CV outcome or death when added to clinical measurements.
Methods And Results:
A multiplex analysis measured a panel of cardiometabolic biomarkers in 1 mL of stored frozen serum from every participant who provided biobanked blood. After eliminating undetectable or unanalyzable biomarkers, 8401 participants who each had a set of 237 biomarkers were analyzed. Forward-selection Cox regression models were used to identify biomarkers that were each independent determinants of 3 different incident outcomes: (1) the composite of myocardial infarction, stroke, or CV death; (2) these plus heart failure hospitalization or revascularization; and (3) all-cause death. When added to clinical variables, 10 biomarkers were independent determinants of the 1405 CV composite outcomes observed during follow-up; 9 biomarkers (including 8 of these 10) were independent determinants of the 2435 expanded composite outcomes; and 15 (including the 10 CV composite biomarkers) were independent determinants of the 1340 deaths. Adjusted C statistics increased from 0.64 for the clinical variables to 0.71 and 0.68 for the 2 CV composite outcomes, respectively, with the greatest increase to 0.75 for death (P<0.001 for the change).
Conclusions:
A systematic hypothesis-free approach identified combinations of up to 15 cardiometabolic biomarkers as independent determinants of CV outcomes or death in people with dysglycemia.
Clinical Trial Registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00069784.
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