Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia
Abstract
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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In the ORIGIN trial, GDF15 was identified as a biomarker linked to positive cardiovascular outcomes and also elevated in those patients receiving metformin.
“As a result of an analysis of data from the ORIGIN trial (Outcome Reduction with Initial Glargine Intervention), GDF15 was identified as a biomarker linked to positive CV outcomes and also elevated in those patients receiving metformin (80, 81).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [80]
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Chapman, M. J., Blankenberg, S., & Landmesser, U. (2016) · Cardiologia Croatica · doi:10.15836/ccar2016.218 · Cited by 2 · see citing works
Are U‐shaped relationships between risk factors and outcomes artifactual?
Shah, R., Thabane, L., & Gerstein, H. C. (2022) · Journal of Diabetes · doi:10.1111/1753-0407.13335 · Cited by 2 · see citing works
Self-citationCukierman‐Yaffe, T., Lee, S.-F., Paré, G., McQueen, M., Hess, S., & Gerstein, H. C. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215195 · Cited by 1 · see citing works
Self-citationMirror mirror on the wall, who is going to be readmitted after all?
Dokollari, A., & Torregrossa, G. (2021) · Journal of Cardiac Surgery · doi:10.1111/jocs.15958 · Cited by 1 · see citing works
Biomarkers: Population Screening and Risk-Stratification
Ratjen, I., Vasan, R. S., & Lieb, W. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809657-4.64154-6 · Cited by 1 · see citing works
Godina 2015. u kardiologiji: prevencija The year in cardiology 2015: prevention
Chapman, M. J., Blankenberg, S., & Landmesser, U. (2016)
OBSOLETE: Biomarkers: Population Screening and Risk-Stratification
Lieb, W. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64154-5
Gerstein, H. C., Hess, S., Claggett, B. L., Dickstein, K., Køber, L., Maggioni, A. P., McMurray, J. J. V., Probstfield, J. L., Riddle, M. C., Tardif, J., et al. (2022) · doi:10.2337/figshare.20069549
Self-citationGerstein, H. C., Hess, S., Claggett, B. L., Dickstein, K., Køber, L., Maggioni, A. P., McMurray, J. J. V., Probstfield, J. L., Riddle, M. C., Tardif, J., et al. (2022) · doi:10.2337/figshare.20069549.v1
Self-citationMohammedi, K., Hess, S., McQueen, M., Pigeyre, M., Lee, S. F., Paré, G., & Gerstein, H. C. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15654
Self-citationGerstein, H. C., Labiba, Z. S., Hess, S., Mohammedi, K., Zhou, Y., & Lee, S. F. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.71070
Self-citation
- Authors
- Gerstein, H. C., Paré, G., McQueen, M. J., Haenel, H., Lee, S. F., Pogue, J., Maggioni, A. P., Yusuf, S., & Hess, S.
- Affiliations
- Population Health Research Institute (CA)
- Venue
- Circulation
- Published
- 2015-12-15
- Volume
- 132
- Issue
- 24
- Pages
- 2297-2304
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2267726385
- Cited by
- 69
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 12 · 2021: 9 · 2020: 5 · 2019: 3 · 2018: 12 · 2017: 7 · 2016: 13 · 2015: 1
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- dysglycemia, cardiometabolic biomarkers, cardiovascular risk prediction, all-cause mortality, myocardial infarction, stroke, heart failure hospitalization, revascularization, serum biomarkers
- MeSH terms
- Aged, Blood Glucose, Cardiovascular Diseases, Cause of Death, Diabetes Mellitus, Type 2, Female, Heart Failure, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Biomarkers
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