. 2014 Mar 26;311(12):1225-33.

doi: 10.1001/jama.2014.1873.

Glycated hemoglobin measurement and prediction of cardiovascular disease

Emerging Risk Factors Collaboration; Emanuele Di Angelantonio¹, Pei Gao¹, Hassan Khan¹, Adam S Butterworth¹, David Wormser¹, Stephen Kaptoge¹, Sreenivasa Rao Kondapally Seshasai², Alex Thompson¹, Nadeem Sarwar¹, Peter Willeit¹, Paul M Ridker³, Elizabeth L M Barr⁴, Kay-Tee Khaw¹, Bruce M Psaty⁵, Hermann Brenner⁶, Beverley Balkau⁷, Jacqueline M Dekker⁸, Debbie A Lawlor⁹, Makoto Daimon¹⁰, Johann Willeit¹¹, Inger Njølstad¹², Aulikki Nissinen¹³, Eric J Brunner¹⁴, Lewis H Kuller¹⁵, Jackie F Price¹⁶, Johan Sundström¹⁷, Matthew W Knuiman¹⁸, Edith J M Feskens¹⁹, W M M Verschuren²⁰, Nicholas Wald²¹, Stephan J L Bakker²², Peter H Whincup², Ian Ford²³, Uri Goldbourt²⁴, Agustín Gómez-de-la-Cámara²⁵, John Gallacher²⁶, Leon A Simons²⁷, Annika Rosengren²⁸, Susan E Sutherland²⁹, Cecilia Björkelund³⁰, Dan G Blazer³¹, Sylvia Wassertheil-Smoller³², Altan Onat³³, Alejandro Marín Ibañez³⁴, Edoardo Casiglia³⁵, J Wouter Jukema³⁶, Lara M Simpson³⁷, Simona Giampaoli³⁸, Børge G Nordestgaard³⁹, Randi Selmer⁴⁰, Patrik Wennberg⁴¹, Jussi Kauhanen⁴², Jukka T Salonen⁴³, Rachel Dankner⁴⁴, Elizabeth Barrett-Connor⁴⁵, Maryam Kavousi⁴⁶, Vilmundur Gudnason⁴⁷, Denis Evans⁴⁸, Robert B Wallace⁴⁹, Mary Cushman⁵⁰, Ralph B D'Agostino Sr⁵¹, Jason G Umans⁵², Yutaka Kiyohara⁵³, Hidaeki Nakagawa⁵⁴, Shinichi Sato⁵⁵, Richard F Gillum⁵⁶, Aaron R Folsom⁵⁷, Yvonne T van der Schouw⁵⁸, Karel G Moons⁵⁸, Simon J Griffin¹, Naveed Sattar²³, Nicholas J Wareham¹, Elizabeth Selvin⁵⁹, Simon G Thompson¹, John Danesh¹

Collaborators, Affiliations

Collaborators

Emerging Risk Factors Collaboration:
L M Simpson, E Selvin, A R Folsom, J Coresh, L Wagenknecht, E L M Barr, J E Shaw, P Z Zimmet, D Magliano, M W Knuiman, P H Whincup, S G Wannamethee, R W Morris, J Willeit, S Kiechl, P Santer, E Bonora, P Willeit, N Wald, D A Lawlor, J P Casas, S Ebrahim, J Gallacher, Y Ben-Shlomo, J W G Yarnell, P Elwood, E Casiglia, D L Bachman, S E Sutherland, P J Nietert, M Cushman, R Selmer, L L Håheim, A J Søgaard, B G Nordestgaard, A Tybjaerg-Hansen, R Frikke-Schmidt, M Benn, S Giampaoli, L Palmieri, D Vanuzzo, S Panico, B Balkau, F Bonnet, N Copin, R Roussel, J A Gómez-Gerique, M A Rubio-Herrera, J A Gutiérrez-Fuentes, L A Simons, Y Friedlander, J McCallum, J Simons, J F Price, A J Lee, S McLachlan, J O Taylor, J M Guralnik, C L Phillips, D A Evans, R B Wallace, F Kohout, D G Blazer, H Cohen, L George, G Fillenbaum, C L Phillips, J M Guralnik, J M McGloin, K -T Khaw, N J Wareham, H Brenner, B Schöttker, H Müller, D Rothenbacher, P Wennberg, J -H Jansson, G Hallmans, A Nissinen, J Tuomilehto, S Giampaoli, C Donfrancesco, M Woodward, R B D'Agostino Sr, M Daimon, T Oizumi, T Kayama, T Kato, R Danker, A Chetrit, A Rosengren, L Wilhelmsen, H Eriksson, G Lappas, C Björkelund, C Bengtsson, L Lissner, I Skoog, P Cremer, Y Kiyohara, H Arima, T Ninomiya, J Hata, J M Dekker, G Nijpels, C D A Stehouwer, S Sato, U Goldbourt, J Kauhanen, J T Salonen, T -P Tuomainen, S Voutilainen, S Kurl, B M Psaty, M Cushman, I H de Boer, A G Bertoni, W M M Veschuren, A Rosengren, L H Kuller, R F Gillum, S Sato, S J L Bakker, R P F Dullaart, H J Lambers Heerspink, H L Hilege, K G Moons, Y T van der Schouw, J W Jukema, N Sattar, S Trompet, D J Stott, G R Dagenais, B Cantin, E Barrett-Connor, V Gudnason, M Kavousi, D Dehghan, A Hofman, O H Franco, H Tunstall-Pedoe, J G Umans, E Lee, L Best, B V Howard, A Onat, G Can, E Ademoğlu, H Nakagawa, M Sakurai, K Nakamura, Y Morikawa, I Njølstad, M -L Løchen, E B Mathiesen, T Wilsgaard, J Sundström, L Byberg, T Cederholm, E Olsson, S Wassertheil-Smoller, B V Howard, E J Brunner, P M Ridker, A D Pradhan, N R Cook, I Ford, A Marín Ibañez, E J M Feskens, D Kromhout, M Walker, S Watson, S Burgess, A S Butterworth, E Di Angelantonio, P Gao, J Gregson, E Harshfield, S Kaptoge, H Khan, L Pennells, S Spackman, S G Thompson, M Walker, S Warnakula, P Willeit, A M Wood, D Wormser, J Danesh

Affiliations

¹ University of Cambridge, Cambridge, United Kingdom.
² St George's University of London, London, United Kingdom.
³ Brigham and Women's Hospital, Boston, Massachusetts.
⁴ Baker IDI Heart and Diabetes Institute, Victoria, Australia.
⁵ University of Washington, Seattle6Group Health Research Institute, Seattle, Washington.
⁶ German Cancer Research Center, Heidelberg, Germany.
⁷ Inserm, Villejuif, France9University Paris-Sud, Villejuif, France.
⁸ Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
⁹ University of Bristol, Bristol, United Kingdom.
¹⁰ Yamagata University, Japan.
¹¹ Medical University Innsbruck, Austria.
¹² University of Tromsø, Tromsø, Norway.
¹³ National Institute of Health and Welfare, Helsinki, Finland.
¹⁴ University College London, London, United Kingdom.
¹⁵ University of Pittsburgh.
¹⁶ University of Edinburgh, Edinburgh, United Kingdom.
¹⁷ Uppsala University, Uppsala, Sweden.
¹⁸ University of Western Australia, Perth, Australia.
¹⁹ Wageningen University, Wageningen, the Netherlands.
²⁰ National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
²¹ Wolfson Institute of Preventive Medicine, London, United Kingdom.
²² University of Groningen, University Medical Center Groningen, the Netherlands.
²³ University of Glasgow, Glasgow, United Kingdom.
²⁴ Sheba Medical Center, Tel Hashomer, Israel.
²⁵ Hospital 12 de Octubre, Madrid, Spain.
²⁶ Cardiff University, Cardiff, United Kingdom.
²⁷ University of New South Wales, Kensington, Australia.
²⁸ Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁹ Medical University of South Carolina, Charleston.
³⁰ University of Gothenburg, Gothenburg, Sweden.
³¹ Duke University Medical Center, Durham, North Carolina.
³² Albert Einstein College of Medicine, New York, New York.
³³ University of Istanbul, Istanbul, Turkey.
³⁴ San Jose Norte Health Centre, Zaragoza, Spain.
³⁵ University of Padova, Padova, Italy.
³⁶ Leiden University Medical Center, Leiden, the Netherlands.
³⁷ University of Texas School of Public Health, Houston.
³⁸ Istituto Superiore di Sanità, Rome, Italy.
³⁹ Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Norwegian Institute of Public Health, Oslo, Norway.
⁴¹ Umeå University, Umeå, Sweden.
⁴² University of Eastern Finland, Kuopio, Finland.
⁴³ University of Helsinki, Helsinki, Finland.
⁴⁴ The Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer, Israel47Tel Aviv University, Tel Aviv, Israel48The Feinstein Institute for Medical Research, New York, New York.
⁴⁵ University of California, San Diego.
⁴⁶ Erasmus Medical Center, Rotterdam, the Netherlands.
⁴⁷ Icelandic Heart Association, Reyjavik, Iceland52University of Iceland, Reykjavik, Iceland.
⁴⁸ Rush University Medical Center, Chicago, Illinois.
⁴⁹ University of Iowa College of Public Health, Iowa City.
⁵⁰ University of Vermont, Burlington.
⁵¹ Boston University, Boston, Massachusetts.
⁵² Georgetown University Medical Centre, Washington, DC.
⁵³ Kyushu University, Kyushu, Japan.
⁵⁴ Kanazawa Medical University, Ishikawa, Japan.
⁵⁵ Osaka Medical Center for Health Science and Promotion/Chiba Prefectural Institute of Public Health, Osaka, Japan.
⁵⁶ Howard University, Washington, DC.
⁵⁷ University of Minnesota, Minneapolis.
⁵⁸ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵⁹ Johns Hopkins University, Baltimore, Maryland.

PMID: 24668104
PMCID: PMC4386007
DOI: 10.1001/jama.2014.1873

Glycated hemoglobin measurement and prediction of cardiovascular disease

Emerging Risk Factors Collaboration et al. JAMA. 2014.

. 2014 Mar 26;311(12):1225-33.

doi: 10.1001/jama.2014.1873.

Authors

Collaborators

Emerging Risk Factors Collaboration:
L M Simpson, E Selvin, A R Folsom, J Coresh, L Wagenknecht, E L M Barr, J E Shaw, P Z Zimmet, D Magliano, M W Knuiman, P H Whincup, S G Wannamethee, R W Morris, J Willeit, S Kiechl, P Santer, E Bonora, P Willeit, N Wald, D A Lawlor, J P Casas, S Ebrahim, J Gallacher, Y Ben-Shlomo, J W G Yarnell, P Elwood, E Casiglia, D L Bachman, S E Sutherland, P J Nietert, M Cushman, R Selmer, L L Håheim, A J Søgaard, B G Nordestgaard, A Tybjaerg-Hansen, R Frikke-Schmidt, M Benn, S Giampaoli, L Palmieri, D Vanuzzo, S Panico, B Balkau, F Bonnet, N Copin, R Roussel, J A Gómez-Gerique, M A Rubio-Herrera, J A Gutiérrez-Fuentes, L A Simons, Y Friedlander, J McCallum, J Simons, J F Price, A J Lee, S McLachlan, J O Taylor, J M Guralnik, C L Phillips, D A Evans, R B Wallace, F Kohout, D G Blazer, H Cohen, L George, G Fillenbaum, C L Phillips, J M Guralnik, J M McGloin, K -T Khaw, N J Wareham, H Brenner, B Schöttker, H Müller, D Rothenbacher, P Wennberg, J -H Jansson, G Hallmans, A Nissinen, J Tuomilehto, S Giampaoli, C Donfrancesco, M Woodward, R B D'Agostino Sr, M Daimon, T Oizumi, T Kayama, T Kato, R Danker, A Chetrit, A Rosengren, L Wilhelmsen, H Eriksson, G Lappas, C Björkelund, C Bengtsson, L Lissner, I Skoog, P Cremer, Y Kiyohara, H Arima, T Ninomiya, J Hata, J M Dekker, G Nijpels, C D A Stehouwer, S Sato, U Goldbourt, J Kauhanen, J T Salonen, T -P Tuomainen, S Voutilainen, S Kurl, B M Psaty, M Cushman, I H de Boer, A G Bertoni, W M M Veschuren, A Rosengren, L H Kuller, R F Gillum, S Sato, S J L Bakker, R P F Dullaart, H J Lambers Heerspink, H L Hilege, K G Moons, Y T van der Schouw, J W Jukema, N Sattar, S Trompet, D J Stott, G R Dagenais, B Cantin, E Barrett-Connor, V Gudnason, M Kavousi, D Dehghan, A Hofman, O H Franco, H Tunstall-Pedoe, J G Umans, E Lee, L Best, B V Howard, A Onat, G Can, E Ademoğlu, H Nakagawa, M Sakurai, K Nakamura, Y Morikawa, I Njølstad, M -L Løchen, E B Mathiesen, T Wilsgaard, J Sundström, L Byberg, T Cederholm, E Olsson, S Wassertheil-Smoller, B V Howard, E J Brunner, P M Ridker, A D Pradhan, N R Cook, I Ford, A Marín Ibañez, E J M Feskens, D Kromhout, M Walker, S Watson, S Burgess, A S Butterworth, E Di Angelantonio, P Gao, J Gregson, E Harshfield, S Kaptoge, H Khan, L Pennells, S Spackman, S G Thompson, M Walker, S Warnakula, P Willeit, A M Wood, D Wormser, J Danesh

Affiliations

¹ University of Cambridge, Cambridge, United Kingdom.
² St George's University of London, London, United Kingdom.
³ Brigham and Women's Hospital, Boston, Massachusetts.
⁴ Baker IDI Heart and Diabetes Institute, Victoria, Australia.
⁵ University of Washington, Seattle6Group Health Research Institute, Seattle, Washington.
⁶ German Cancer Research Center, Heidelberg, Germany.
⁷ Inserm, Villejuif, France9University Paris-Sud, Villejuif, France.
⁸ Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
⁹ University of Bristol, Bristol, United Kingdom.
¹⁰ Yamagata University, Japan.
¹¹ Medical University Innsbruck, Austria.
¹² University of Tromsø, Tromsø, Norway.
¹³ National Institute of Health and Welfare, Helsinki, Finland.
¹⁴ University College London, London, United Kingdom.
¹⁵ University of Pittsburgh.
¹⁶ University of Edinburgh, Edinburgh, United Kingdom.
¹⁷ Uppsala University, Uppsala, Sweden.
¹⁸ University of Western Australia, Perth, Australia.
¹⁹ Wageningen University, Wageningen, the Netherlands.
²⁰ National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
²¹ Wolfson Institute of Preventive Medicine, London, United Kingdom.
²² University of Groningen, University Medical Center Groningen, the Netherlands.
²³ University of Glasgow, Glasgow, United Kingdom.
²⁴ Sheba Medical Center, Tel Hashomer, Israel.
²⁵ Hospital 12 de Octubre, Madrid, Spain.
²⁶ Cardiff University, Cardiff, United Kingdom.
²⁷ University of New South Wales, Kensington, Australia.
²⁸ Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁹ Medical University of South Carolina, Charleston.
³⁰ University of Gothenburg, Gothenburg, Sweden.
³¹ Duke University Medical Center, Durham, North Carolina.
³² Albert Einstein College of Medicine, New York, New York.
³³ University of Istanbul, Istanbul, Turkey.
³⁴ San Jose Norte Health Centre, Zaragoza, Spain.
³⁵ University of Padova, Padova, Italy.
³⁶ Leiden University Medical Center, Leiden, the Netherlands.
³⁷ University of Texas School of Public Health, Houston.
³⁸ Istituto Superiore di Sanità, Rome, Italy.
³⁹ Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Norwegian Institute of Public Health, Oslo, Norway.
⁴¹ Umeå University, Umeå, Sweden.
⁴² University of Eastern Finland, Kuopio, Finland.
⁴³ University of Helsinki, Helsinki, Finland.
⁴⁴ The Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer, Israel47Tel Aviv University, Tel Aviv, Israel48The Feinstein Institute for Medical Research, New York, New York.
⁴⁵ University of California, San Diego.
⁴⁶ Erasmus Medical Center, Rotterdam, the Netherlands.
⁴⁷ Icelandic Heart Association, Reyjavik, Iceland52University of Iceland, Reykjavik, Iceland.
⁴⁸ Rush University Medical Center, Chicago, Illinois.
⁴⁹ University of Iowa College of Public Health, Iowa City.
⁵⁰ University of Vermont, Burlington.
⁵¹ Boston University, Boston, Massachusetts.
⁵² Georgetown University Medical Centre, Washington, DC.
⁵³ Kyushu University, Kyushu, Japan.
⁵⁴ Kanazawa Medical University, Ishikawa, Japan.
⁵⁵ Osaka Medical Center for Health Science and Promotion/Chiba Prefectural Institute of Public Health, Osaka, Japan.
⁵⁶ Howard University, Washington, DC.
⁵⁷ University of Minnesota, Minneapolis.
⁵⁸ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵⁹ Johns Hopkins University, Baltimore, Maryland.

PMID: 24668104
PMCID: PMC4386007
DOI: 10.1001/jama.2014.1873

Abstract

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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Figures

**Figure 1. Hazard Ratios for Incident Cardiovascular Disease (CVD) Outcomes by Baseline Levels of Glycemia Measures**
Analyses were adjusted for age, smoking status, systolic blood pressure, total cholesterol level, and high-density lipoprotein cholesterol level and stratified by sex and trial group where appropriate. Participants were classified into groups of (1) HbA1c% (mmol/mol): <4.5 (<25.7), 4.5 to <5 (25.7-<31.1), 5 to <5.5 (31.1-<36.3) [reference category], 5.5 to <6 (36.6-<42.1), 6 to <6.5 (42.1-<48.0), and ≥6.5 (≥48.0); (2) fasting glucose (mg/dL): <76, 76 to <90, 90 to <105 [reference category], 105 to <119, 119 to <133, ≥133; (3) random glucose (mg/dL) <68, 68 to <90, 90 to <112 [reference category], 112 to <133, 133 to <155, ≥155; (4) Postload glucose (mg/dL): <68, 68 to <108, 108 to <148 [reference category], 148 to <187, 187 to <227, ≥227. These categories approximately correspond to 1-SD increments for each factor. Incident CVD outcomes refer to first-onset CVD cases, defined as fatal or nonfatal coronary heart disease or any stroke. SI conversion factors: To convert glucose values to mmol/L, multiply by 0.0555. Sizes of boxes are proportional to the inverse of the variance.

**Figure 2. Hazard Ratios for Incident Cardiovascular Disease for Glycemia Measures by Selected Study-Level Characteristics**
Participants with levels of glycemia measures below the mean were excluded. Baseline SD was used to calculate per-SD hazard ratio (HR). Analyses were conducted using studies with information across all levels of each subgroup variable. DCCT indicates Diabetes Control and Complications Trial; HPLC, high-performance liquid chromatography; ITA, immunoturbidimetric assay. A full list of the characteristics examined for heterogeneity is provided in eFigures 5 through 8 in Supplement.

**Figure 3. Changes in Cardiovascular Disease Risk Discrimination After the Addition of Information on Glycemia Measures to Conventional Risk Factors**
Incident cardiovascular disease outcomes refer to first-onset cardiovascular disease cases, defined as fatal or nonfatal coronary heart disease event or any stroke. Studies with missing self-reported diabetes information were excluded. ^a Conventional risk factors include age, sex (stratified), smoking status, systolic blood pressure, and levels of total cholesterol and high-density lipoprotein cholesterol. ^b P < .05 ^c P < .001.

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References

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1. Rydén L, Grant PJ, Anker SD, et al. Authors/Task Force Members; ESC Committee for Practice Guidelines (CPG); Document Reviewers. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD) Eur Heart J. 2013;34(39):3035–3087. - PubMed
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1. US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151(7):474–482. - PubMed

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Glycated hemoglobin measurement and prediction of cardiovascular disease

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Glycated hemoglobin measurement and prediction of cardiovascular disease

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