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'Agostino51, 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. 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.
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.
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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