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Association of Hemoglobin A_1c with Cardiovascular Disease and Mortality in Adults: The European Prospective Investigation into Cancer in Norfolk

Kay-Tee Khaw, MBBChir FRCP; Nicholas Wareham, MBBS, FRCP; Sheila Bingham, PhD; Robert Luben, BSc; Ailsa Welch, BSc; and Nicholas Day, PhD

21 September 2004 | Volume 141 Issue 6 | Pages 413-420

Background: Increasing evidence suggests a continuous relationship between blood glucose concentrations and cardiovascular risk, even below diagnostic threshold levels for diabetes.

Objective: To examine the relationship between hemoglobin A_1c, cardiovascular disease, and total mortality.

Design: Prospective population study.

Setting: Norfolk, United Kingdom.

Participants: 4662 men and 5570 women who were 45 to 79 years of age and were residents of Norfolk.

Measurements: Hemoglobin A_1c and cardiovascular disease risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were assessed during the follow-up period to 2003.

Results: In men and women, the relationship between hemoglobin A_1c and cardiovascular disease (806 events) and between hemoglobin A_1c and all-cause mortality (521 deaths) was continuous and significant throughout the whole distribution. The relationship was apparent in persons without known diabetes. Persons with hemoglobin A_1c concentrations less than 5% had the lowest rates of cardiovascular disease and mortality. An increase in hemoglobin A_1c of 1 percentage point was associated with a relative risk for death from any cause of 1.24 (95% CI, 1.14 to 1.34; P < 0.001) in men and with a relative risk of 1.28 (CI, 1.06 to 1.32; P < 0.001) in women. These relative risks were independent of age, body mass index, waist-to-hip ratio, systolic blood pressure, serum cholesterol concentration, cigarette smoking, and history of cardiovascular disease. When persons with known diabetes, hemoglobin A_1c concentrations of 7% or greater, or a history of cardiovascular disease were excluded, the result was similar (adjusted relative risk, 1.26 [CI, 1.04 to 1.52]; P = 0.02). Fifteen percent (68 of 521) of the deaths in the sample occurred in persons with diabetes (4% of the sample), but 72% (375 of 521) occurred in persons with HbA_1c concentrations between 5% and 6.9%.

Limitations: Whether HbA_1c concentrations and cardiovascular disease are causally related cannot be concluded from an observational study; intervention studies are needed to determine whether decreasing HbA_1c concentrations would reduce cardiovascular disease.

Conclusions: The risk for cardiovascular disease and total mortality associated with hemoglobin A_1c concentrations increased continuously through the sample distribution. Most of the events in the sample occurred in persons with moderately elevated HbA_1c concentrations. These findings support the need for randomized trials of interventions to reduce hemoglobin A_1c concentrations in persons without diabetes.

Editors' Notes Context Several studies suggest that blood glucose levels are associated with cardiovascular disease, even at blood glucose values that do not meet diagnostic criteria for diabetes. Contribution Among adult residents of Norfolk, United Kingdom, there was a continuous relationship between hemoglobin A1c levels and cardiovascular disease and total mortality. This relationship was apparent even among persons without diabetes. Implications These observations justify the need for studies that address whether improvements in glycemic control might improve health outcomes in persons who do not have diabetes. –The Editors

 

Author and Article Information

From University of Cambridge, Medical Research Council Epidemiology Unit, and Medical Research Council Dunn Nutrition Unit, Cambridge, United Kingdom.

Acknowledgments: The authors thank the participants, general practitioners, and staff of EPIC–Norfolk.

Grant Support: EPIC–Norfolk is supported by program grants from the Medical Research Council United Kingdom and Cancer Research United Kingdom. The European Union, Stroke Association, and British Heart Foundation provided additional support.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Kay-Tee Khaw, MBBChir, FRCP, Clinical Gerontology Unit, Box 251, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom; e-mail, kk101{at}medschl.cam.ac.uk.

Current Author Addresses: Dr. Khaw: Clinical Gerontology Unit, Box 251, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.

Dr. Wareham: Medical Research Council Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom.

Dr. Bingham: Medical Research Council Dunn Nutrition Unit, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom.

Mr. Luben, Ms. Welch, and Dr. Day: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratories, Worts Causeway, Cambridge CB1 8RN, United Kingdom.

Author Contributions: Conception and design: K.-T. Khaw, N. Wareham, S. Bingham, A. Welch, N. Day.

Analysis and interpretation of the data: K.-T. Khaw, N. Wareham.

Drafting of the article: K.-T. Khaw, N. Wareham.

Critical revision of the article for important intellectual content: N. Wareham, S. Bingham, A. Welch, N. Day.

Final approval of the article: K.-T. Khaw, N. Wareham, S. Bingham, R. Luben, A. Welch, N. Day.

Statistical expertise: R. Luben, N. Day.

Obtaining of funding: K.-T. Khaw, N. Wareham, S. Bingham, N. Day.

Administrative, technical, or logistic support: N. Wareham, S. Bingham, R. Luben, A. Welch, N. Day.

Collection and assembly of data: R. Luben, A. Welch.

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