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Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease
Open accessAbstract
IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
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“It should be noted that data from 73 studies on 294 998 individuals without known diabetes suggest that HbA1c is as good as or better than fasting, random, or post-load glucose levels for predicting CV risk.14”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [14]
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“UKPDS부터 최근의 심혈관질환결과물연구(cardio- vascular outcome trials, CVOTs)로 인해, 1921년 인슐린 발견 이후[31] 2형당뇨병 관리는 엄격한 혈당조절을 위해 ‘효 과(efficacy)’를 강조한 ‘혈당중심적(gluco-centric) 개념’에 서 체중증가, 저혈당, 그리고 CVDs 안전성을 확보하려는 ‘안 전(safety)’을 고려한 개념을 거쳐, 최근에는 당뇨병환자의 사 망과 연관된 CVDs 및 DKD 등 ‘기관보호(organ protec- tion)’라는 패러다임으로 변했다.”
InfluentialClinical Approach to Assessment and Amelioration of Atherosclerotic Vascular Disease in Diabetes
Goldberg, R. B. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.582826 · Cited by 3
Masrouri, S., Hasanpour, A., Ebrahimi, N., & Hadaegh, F. (2025) · Cardiovascular Diabetology · doi:10.1186/s12933-025-02968-2 · Cited by 3
Rana, J. S., Shin, E. D., Finertie, H., Chowdhury, N., & Schmittdiel, J. A. (2026) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2026.101468 · Cited by 2
New Treatments for Type 2 Diabetes Mellitus and Cardiovascular Disease. The Revolution Has Begun
Simó, R., & Hernández, C. (2016) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2016.07.009 · Cited by 2
Simó, R., & Hernández, C. (2016) · Revista Española de Cardiología · doi:10.1016/j.recesp.2016.07.030 · Cited by 2
Diagnostic Criteria and Classification of Diabetes
Gospin, R., & Zonszein, J. (2015) · Springer eBooks · doi:10.1007/978-3-319-20797-1_7-1 · Cited by 2
Bai, X., Wang, H., & Zhao, Q.-L. (2022) · World Journal of Diabetes · doi:10.4239/wjd.v13.i3.251 · Cited by 2
Diagnostic Criteria and Classification of Diabetes
Gospin, R., Leu, J. P., & Zonszein, J. (2017) · Springer eBooks · doi:10.1007/978-3-319-18741-9_7 · Cited by 2
Sun, L., Pennells, L. A. M., Kaptoge, S. K., Nelson, C. P., Abraham, G., Arnold, M., Bell, S., Bolton, T. R., Burgess, S., Dudbridge, F., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/744565 · Cited by 2
Self-citationHorikawa, C., Takahara, M., Katakami, N., Takeda, Y., Takeuchi, M., Fujihara, K., Suzuki, H., Yoshioka, N., Shimano, H., Satoh, J., et al. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16035 · Cited by 2
Demidova, T. Y. (2025) · FOCUS Endocrinology · doi:10.62751/2713-0177-2025-6-1-05 · Cited by 1
Agrawal, M., Kumar, A., Singh, A. K., Singh, H., Kumar, P., & Kumar, P. (2026) · Current Hypertension Reviews · doi:10.2174/0115734021389208251113105243 · Cited by 1
Šelb, J., Deutsch, L., Červek, M., Pratt, M. B., Bedrač, L., Mohorčič, D., Sebanc, N., Ašič, U., Terzic, S., Kuščer, E., et al. (2026) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2026.112230 · Cited by 1
Koskela, H. O., Salonen, P. H., Romppanen, J., & Hartikainen, J. E. K. (2015) · ESC Heart Failure · doi:10.1002/ehf2.12031 · Cited by 1
“The association between HbA1c and cardiovascular disease risk is J-shaped, and it has been postulated that low plasma glucose levels are markers of ill health.(26) Perhaps a HbA1c level ≥ 6.”
BackgroundModulators of J-Shaped Association of HbA1c Levels with Mortality in Adults
Altay, S., Onat, A., Kaya, A., & Tusun, E. (2016) · Cardiology · doi:10.1159/000445797 · Cited by 1
Self-citationBaligar, B. D., Bande, U. S., Kardkal, B. L., Hasabi, I. S., & Anurshetru, S. (2016) · Journal of Evidence Based Medicine and Healthcare · doi:10.18410/jebmh/2016/637 · Cited by 1
Therapie postprandialer Blutzuckerspitzen – sinnvoll oder nur Blutzuckerkosmetik?
Forst, T. M. (2017) · Der Diabetologe · doi:10.1007/s11428-017-0259-x · Cited by 1
“ImGegensatzdazusteht eineUntersuchung der „Emerging Risk Factors Collaboration“ [18], in welcher kein zusätzlicher prädiktiver Wert eines oralen Glukosetoleranztests gegenüber der HbA1cWert-BestimmungbeiPatientenmitDiabetesmellitus und einer bekannten KHK über 10 Jahre festgestellt wurde.”
BackgroundChattopadhyay, S., George, A., John, J., & Sathyapalan, T. (2020) · Cardiology · doi:10.1159/000509180 · Cited by 1
Cardiovascular Biomarker Assessment Across Glycemic Status
Li, D., & Tang, W. H. W. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-800093-9.00021-1 · Cited by 1
Reprint of: Blood Sugar Regulation for Cardiovascular Health Promotion and Disease Prevention
Schwarz, P. E. H., Timpel, P., Harst, L., Greaves, C. J., Ali, M. K., Lambert, J. D., Weber, M. B., Almedawar, M. M., & Morawietz, H. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.10.026 · Cited by 1
Cardiovascular Disease Prediction Analysis Using SPSS Statistics
(2017) · REST Journal on Emerging trends in Modelling and Manufacturing · doi:10.46632/jemm/3/4/5 · Cited by 1
Macrovascular Disease in Type 2 Diabetes
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Rannsóknarstöð Hjartaverndar, fortíð og nútíð
Sigurdsson, G. T. (2014)
Lee, J. I., Yoon, J. H., Kim, S. H., & Park, Y. M. (2015)
Resolving the KgA1c paradox in the management of type 2 diabetes mellitus
Davidson, J. A., Kalra, S., Singh, V., Fegade, M., Singh, G., & Mane, A. (2016) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2016.12.026
The Epidemiology of Nontraditional Biomarkers of Hyperglycemia and their Prognostic Value
Parrinello, C. M. (2015)
La gestione del paziente diabetico tra presente e futuro
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Metadata
- Authors
- Di Angelantonio, E., Gao, P., Khan, H., Butterworth, A. S., Wormser, D., Kaptoge, S., Kondapally Seshasai, S. R., Thompson, A., Sarwar, N., Willeit, P., Ridker, P. M., Barr, E. L. M., Khaw, K.-T., Psaty, B. M., Brenner, H., Balkau, B., Dekker, J. M., Lawlor, D. A., Daimon, M., Willeit, J., Njølstad, I., Nissinen, A., Brunner, E. J., Kuller, L. H., Price, J. F., Sundström, J., Knuiman, M. W., Feskens, E. J. M., Verschuren, W. M. M., Wald, N., Bakker, S. J. L., Whincup, P. H., Ford, I., Goldbourt, U., Gómez-de-la-Cámara, A., Gallacher, J., Simons, L. A., Rosengren, A., Sutherland, S. E., Björkelund, C., Blazer, D. G., Wassertheil-Smoller, S., Onat, A., Marín Ibañez, A., Casiglia, E., Jukema, J. W., Simpson, L. M., Giampaoli, S., Nordestgaard, B. G., Selmer, R., Wennberg, P., Kauhanen, J., Salonen, J. T., Dankner, R., Barrett-Connor, E., Kavousi, M., Gudnason, V., Evans, D., Wallace, R. B., Cushman, M., D’Agostino, R. B., Umans, J. G., Kiyohara, Y., Nakagawa, H., Sato, S., Gillum, R. F., Folsom, A. R., van der Schouw, Y. T., Moons, K. G., Griffin, S. J., Sattar, N., Wareham, N. J., Selvin, E., Thompson, S. G., & Danesh, J.
- Affiliations
- University of Cambridge, Cambridge, United Kingdom
- University of Cambridge (GB)
- St George's University of London, London, United Kingdom
- Brigham and Women's Hospital (US)
- Baker Heart and Diabetes Institute (AU)
- University of Washington (US)
- German Cancer Research Center (DE)
- Inserm (FR)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Bristol (GB)
- Yamagata University (JP)
- Innsbruck Medical University (AT)
- UiT The Arctic University of Norway (NO)
- Finnish Institute for Health and Welfare (FI)
- University College London (GB)
- University of Pittsburgh (US)
- University of Edinburgh (GB)
- Uppsala University (SE)
- The University of Western Australia (AU)
- Wageningen University & Research (NL)
- National Institute for Public Health and the Environment (NL)
- Wolfson Institute of Preventive Medicine, London, United Kingdom
- University Medical Center Groningen (NL)
- St George's, University of London (GB)
- University of Glasgow (GB)
- Sheba Medical Center (IL)
- Hospital 12 de Octubre, Madrid, Spain
- Cardiff University (GB)
- UNSW Sydney (AU)
- University of Gothenburg (SE)
- Medical University of South Carolina (US)
- Duke Medical Center (US)
- Albert Einstein College of Medicine, New York, New York
- Istanbul University (TR)
- San Jose Norte Health Centre, Zaragoza, Spain
- University of Padua (IT)
- Leiden University Medical Center (NL)
- University of Texas School of Public Health, Houston
- Istituto Superiore di Sanità (IT)
- University of Copenhagen (DK)
- Norwegian Institute of Public Health (NO)
- Umeå University (SE)
- University of Eastern Finland (FI)
- University of Helsinki (FI)
- Feinstein Institute for Medical Research (US)
- University of California San Diego (US)
- Erasmus MC (NL)
- University of Iceland (IS)
- Rush University Medical Center (US)
- University of Iowa (US)
- University of Vermont (US)
- Boston University (US)
- Georgetown University (US)
- Kyushu University (JP)
- Kanazawa Medical University (JP)
- Chiba Prefectural Institute of Public Health (JP)
- Howard University (US)
- University of Minnesota (US)
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
- University Medical Center Utrecht (NL)
- Johns Hopkins University (US)
- Corresponding author
- Danesh, John
- ORCID
- Gao, Pei
- Khan, Hassan
- Butterworth, Adam S.
- Kaptoge, Stephen
- Thompson, Alex
- Sarwar, Nadeem
- Willeit, Peter
- Ridker, Paul M
- Barr, Elizabeth L. M.
- Khaw, Kay-Tee
- Psaty, Bruce M.
- Brenner, Hermann
- Balkau, Beverley
- Lawlor, Debbie A.
- Daimon, Makoto
- Willeit, Johann
- Njølstad, Inger
- Brunner, Eric J.
- Kuller, Lewis H.
- Price, Jackie F.
- Sundström, Johan
- Knuiman, Matthew W.
- Feskens, Edith J. M.
- Verschuren, W. M. M.
- Wald, Nicholas
- Bakker, Stephan J. L.
- Whincup, Peter H.
- Ford, Ian
- Gallacher, John
- Simons, Leon A.
- Rosengren, Annika
- Sutherland, Susan E.
- Blazer, Dan G.
- Onat, Altan
- Casiglia, Edoardo
- Jukema, J. Wouter
- Giampaoli, Simona
- Nordestgaard, Børge G.
- Selmer, Randi
- Wennberg, Patrik
- Dankner, Rachel
- Barrett-Connor, Elizabeth
- Kavousi, Maryam
- Gudnason, Vilmundur
- Evans, Denis
- Wallace, Robert B.
- Cushman, Mary
- D’Agostino, Ralph B.
- Umans, Jason G.
- Sato, Shinichi
- Gillum, Richard F.
- Folsom, Aaron R.
- Moons, Karel G.
- Griffin, Simon J.
- Sattar, Naveed
- Wareham, Nicholas J.
- Selvin, Elizabeth
- Thompson, Simon G.
- Danesh, John
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2014-03-26
- Volume
- 311
- Issue
- 12
- Pages
- 1225
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4386007
- OpenAlex
- W2114008139
- Cited by
- 231
- References
- 32
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 17 · 2023: 12 · 2022: 20 · 2021: 14 · 2020: 22 · 2019: 13 · 2018: 20 · 2017: 22 · 2016: 23 · 2015: 34 · 2014: 12
- FWCI
- 24.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0512-10114)
- British Heart Foundation (RG/08/013/25942, RG/13/16/30528, PG/13/66/30442, RG/08/014/24067)
- National Institutes of Health (UL1TR000062)
- Medical Research Council (MC_UU_12015/4, MR/K013351/1, MR/L003120/1)
- National Center for Advancing Translational Sciences
- 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 › Public Health, Environmental and Occupational Health › Health Promotion and Cardiovascular Prevention
- Keywords
- HbA1c, cardiovascular risk prediction, coronary artery disease, stroke, risk discrimination, net reclassification improvement, cardiovascular risk factors, J-shaped association, fasting blood glucose, post-load glucose, C-reactive protein, HDL cholesterol, estimated glomerular filtration rate, non-diabetic adults
- MeSH terms
- Aged, C-Reactive Protein, Coronary Disease, Diabetes Mellitus, Female, Glycated Hemoglobin, Humans, Cholesterol, HDL, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Risk Assessment, Stroke
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