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. 2023 Sep 6;30(12):1218-1226.
doi: 10.1093/eurjpc/zwad122.

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus

Paul M Haller  1   2 , Alina Goßling  1 , Christina Magnussen  1   2 , Hermann Brenner  3 , Ben Schöttker  3 , Licia Iacoviello  4   5 , Simona Costanzo  4 , Frank Kee  6 , Wolfgang Koenig  7   8   9 , Allan Linneberg  10   11 , Chaterina Sujana  12 , Barbara Thorand  12   13 , Veikko Salomaa  14 , Teemu J Niiranen  14   15 , Stefan Söderberg  16 , Henry Völzke  17   18 , Marcus Dörr  18   19 , Susana Sans  20 , Teresa Padró  21 , Stephan B Felix  18   19 , Matthias Nauck  18   22 , Astrid Petersmann  22   23 , Luigi Palmieri  24 , Chiara Donfrancesco  24 , Roberto De Ponti  5 , Giovanni Veronesi  5 , Marco M Ferrario  5 , Kari Kuulasmaa  14 , Tanja Zeller  1   2 , Francisco M Ojeda  1 , Stefan Blankenberg  1   2 , Dirk Westermann  25 ; BiomarCaRE Consortium
Affiliations

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus

Paul M Haller et al. Eur J Prev Cardiol. .

Abstract

Aims: The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes.

Methods and results: We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan-Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P < 0.001), accompanied by an increase in the c-index (increase to 0.81).

Conclusion: Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.

Keywords: Biomarkers; Cardiovascular events; Diabetes; NT-proBNP; hs-CRP; hs-cTnI.

Plain language summary

In this work, the role of cardiac biomarkers measured from blood to predict cardiovascular events and death is tested in individuals of the general population and particularly in those with known diabetes. The work is based on a cooperation of different population studies across Europe and includes more than 90 000 individuals, with more than 6000 having diabetes. We could demonstrate that the determination of three cardiac biomarkers helps to identify individuals at highest risk for cardiovascular events (e.g. myocardial infarction or stroke) and death, despite accounting for known cardiovascular risk factors in these individuals. Therefore, these biomarkers should be considered for routine risk assessment for cardiovascular diseases and could improve the early identification of high-risk individuals, consequently leading to an earlier initiation of preventive therapies.

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Conflict of interest statement

Conflict of interest: P.M.H. has received travel grants from the German Center of Cardiovascular Research (DZHK) and is supported by a grant of the Faculty of Medicine, University of Hamburg, Germany. S.C. was the principal investigator of a study supported by a research grant from ERAB (the European Foundation for Alcohol Research; id. EA1767, 2018-2020), outside the submitted work. S.C. reports personal fees as member of the Organizing Committee and speaker for the 9th European Beer and Health Symposium (Bruxelles 2019) and for given lecture at the 13th European Nutrition Conference FENS 2019 (Dublin), sponsored by the Beer and Health Initiative (The Dutch Beer Institute foundation—The Brewers of Europe), outside the submitted work. W.K. reports consulting fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, speaker honoraria from Amgen, Novartis, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb, grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex, outside the submitted work. V.S. has received an honorarium from Sanofi for consulting and has ongoing research collaboration with Bayer Ltd (all outside the present study). T.J.N. reports funding by the European Union programme euCanSHare (Horizon 2020, No. 825903) and AFFECT-EU (Horizon 2020, No. 847770) related to the present work and institutional funding by the Academy of Finland, the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research outside of the submitted work, and honoraria from Servier Finland and AstraZeneca outside of the submitted work. St.S. reports honoraria for speaker bureaus from Actelion/Jansen, and participated in an advisory board for Actelion/Jansen and Novartis, and in a scientific board for Actelion/Jansen, all outside of the submitted work. T.P. reports research funding from the Spanish Institute of Health Carlos III (ISCIII), unrelated to the current work. S.B.F. reports grants from German Center for Cardiovascular Research (DZHK). S.B.F. has received speaker honoraria from AstraZeneca, Bayer, Novartis, Pfizer. MN has received travel grants by German Medical Association, German Centre for Cardiovascular Research, German Society for Clinical Chemistry and Laboratory Medicine, German National Cohort, German Research Foundation, Deutsche Akkreditierungsstelle, Sysmex, MDI Limbach, medpoint GmbH, Diasys and speaker’s honoraria from Novartis Pharma, Radiometer, AstraZeneca, Technopath Clinical Diagnostics, Sysmex, MDI Limbach and medpoint Medizinkommunikations GmbH as well as research funding from Aerocom GmbH and Profil Institut für Stoffwechselforschung GmbH. A.P. has received speaker honoraria from Radiometer, Tosoh, Technopath Clinical Diagnostics and Roche Diagnostics as well as research funding from LabNet Laborsysteme GmbH and Roche Diagnostics. C.M. reports research funding from Deutsche Stiftung für Herzforschung, German Center for Cardiovascular Research (DZHK), ndd Medical, and Loewenstein Medical. C.M. got honoraria from AstraZeneca, Novartis, Loewenstein Medical, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, and Apontis unrelated to the current work. T.N. reports speakers’ honoraria from Servier Finland unrelated to the current work. D.W. reports consultation fees from Bayer and Abiomed and honoraria from Abiomed, Bayer, Boehringer, Novartis, Medtronic, and Edwards Life Sciences, all outside of the submitted work. All other authors declare no conflict of interest.

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