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      Hemoglobin A 1c Levels and the Risk of Cardiovascular Disease in People Without Known Diabetes : A Population-Based Cohort Study in Japan

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      Author(s): , MD, PhD, MPH, , MD, PhD, , PhD, , MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD, , PhD, , PhD, , PhD, , MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD, MS, , MD, PhD, MPH, , MD, PhD, , MD, PhD
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      Journal: Medicine
      Publisher: Wolters Kluwer Health

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          Abstract

          High hemoglobin A 1c (HbA 1c) levels are strongly associated with an increased risk of cardiovascular disease (CVD) in people with and without diabetes. However, information regarding the relationship between low HbA 1c levels and the risk of CVD among people without known diabetes is limited. The aim of this large-scale, prospective, population-based cohort study was to clarify the association between HbA 1c levels and CVD risk among people without known diabetes.

          We followed-up 10,980 men and 18,079 women (46–80 years old and free of CVD and cancer at baseline) in the Japan Public Health Center-based Prospective Study. Using Cox models, we estimated the hazard ratios for CVD risk with adjustments for age, sex, geographic areas, body mass index, smoking status, sports and physical exercise, alcohol intake, systolic blood pressure, non-high-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.

          During the median follow-up of 9.4 years, 935 CVD events (770 strokes and 165 coronary heart diseases) occurred. We observed a nonlinear association between HbA 1c levels and CVD risk in participants without known diabetes. Compared with HbA 1c levels of 5.0 to 5.4% (31–36 mmol/mol), the hazard ratios for CVD in participants without known diabetes were 1.50 (95% confidence interval: 1.15–1.95), 1.01 (0.85–1.20), 1.04 (0.82–1.32), and 1.77 (1.32–2.38) for HbA 1c levels of <5.0% (<31 mmol/mol), 5.5 to 5.9% (37–41 mmol/mol), 6.0 to 6.4% (42–47 mmol/mol), and ≥6.5% (≥48 mmol/mol), respectively ( P value for nonlinear trend: <0.001). In addition, the hazard ratio for CVD was 1.81 (1.43–2.29) in patients with known diabetes compared with participants with HbA 1c levels of 5.0 to 5.4% and without known diabetes. This nonlinear relation persisted after excluding people with kidney dysfunction, liver dysfunction, anemia, body mass index <18.5 kg/m 2, or early events within 3 years of follow-up ( P value for nonlinear trend: <0.01 for all tests).

          In conclusion, both low and high levels of HbA 1c were associated with a higher risk of CVD in a Japanese general population without known diabetes.

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          Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score.

          Paul Ridker, Julie Buring, Nader Rifai … (2007)
          Despite improved understanding of atherothrombosis, cardiovascular prediction algorithms for women have largely relied on traditional risk factors. To develop and validate cardiovascular risk algorithms for women based on a large panel of traditional and novel risk factors. Thirty-five factors were assessed among 24 558 initially healthy US women 45 years or older who were followed up for a median of 10.2 years (through March 2004) for incident cardiovascular events (an adjudicated composite of myocardial infarction, ischemic stroke, coronary revascularization, and cardiovascular death). We used data among a random two thirds (derivation cohort, n = 16 400) to develop new risk algorithms that were then tested to compare observed and predicted outcomes in the remaining one third of women (validation cohort, n = 8158). Minimization of the Bayes Information Criterion was used in the derivation cohort to develop the best-fitting parsimonious prediction models. In the validation cohort, we compared predicted vs actual 10-year cardiovascular event rates when the new algorithms were compared with models based on covariates included in the Adult Treatment Panel III risk score. In the derivation cohort, a best-fitting model (model A) and a clinically simplified model (model B, the Reynolds Risk Score) had lower Bayes Information Criterion scores than models based on covariates used in Adult Treatment Panel III. In the validation cohort, all measures of fit, discrimination, and calibration were improved when either model A or B was used. For example, among participants without diabetes with estimated 10-year risks according to the Adult Treatment Panel III of 5% to less than 10% (n = 603) or 10% to less than 20% (n = 156), model A reclassified 379 (50%) into higher- or lower-risk categories that in each instance more accurately matched actual event rates. Similar effects were achieved for clinically simplified model B limited to age, systolic blood pressure, hemoglobin A(1c) if diabetic, smoking, total and high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and parental history of myocardial infarction before age 60 years. Neither new algorithm provided substantive information about women at very low risk based on the published Adult Treatment Panel III score. We developed, validated, and demonstrated highly improved accuracy of 2 clinical algorithms for global cardiovascular risk prediction that reclassified 40% to 50% of women at intermediate risk into higher- or lower-risk categories.
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            Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study.

            Craig J. Currie, John R Peters, Aódan Tynan … (2010)
            Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA(1c) in people with type 2 diabetes. Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly. For combined cohorts, compared with the glycated haemoglobin (HbA(1c)) decile with the lowest hazard (median HbA(1c) 7.5%, IQR 7.5-7.6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA(1c) decile (6.4%, 6.1-6.6) was 1.52 (95% CI 1.32-1.76), and in the highest HbA(1c) decile (median 10.5%, IQR 10.1-11.2%) was 1.79 (95% CI 1.56-2.06). Results showed a general U-shaped association, with the lowest HR at an HbA(1c) of about 7.5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1.49 (95% CI 1.39-1.59). Low and high mean HbA(1c) values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA(1c) value. Eli Lilly and Company. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk.

              Kay-Tee Khaw, Nicholas J. Wareham, Sheila Bingham … (2004)
              Increasing evidence suggests a continuous relationship between blood glucose concentrations and cardiovascular risk, even below diagnostic threshold levels for diabetes. To examine the relationship between hemoglobin A1c, cardiovascular disease, and total mortality. Prospective population study. Norfolk, United Kingdom. 4662 men and 5570 women who were 45 to 79 years of age and were residents of Norfolk. Hemoglobin A1c 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. In men and women, the relationship between hemoglobin A1c and cardiovascular disease (806 events) and between hemoglobin A1c 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 A1c concentrations less than 5% had the lowest rates of cardiovascular disease and mortality. An increase in hemoglobin A1c 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 HbA1c concentrations between 5% and 6.9%. Whether HbA1c concentrations and cardiovascular disease are causally related cannot be concluded from an observational study; intervention studies are needed to determine whether decreasing HbA1c concentrations would reduce cardiovascular disease. The risk for cardiovascular disease and total mortality associated with hemoglobin A1c concentrations increased continuously through the sample distribution. Most of the events in the sample occurred in persons with moderately elevated HbA1c concentrations. These findings support the need for randomized trials of interventions to reduce hemoglobin A1c concentrations in persons without diabetes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Medicine (Baltimore)
                Journal ID (iso-abbrev): Medicine (Baltimore)
                Journal ID (publisher-id): MEDI
                Title: Medicine
                Publisher: Wolters Kluwer Health
                ISSN (Print): 0025-7974
                ISSN (Electronic): 1536-5964
                Publication date Collection: May 2015
                Publication date (Electronic): 01 May 2015
                Volume: 94
                Issue: 17
                Electronic Location Identifier: e785
                Affiliations
                From the Departments of Diabetes Research, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan (AG, MN, MG, MK); Department of Public Health, Tokyo Women's Medical University, Tokyo, Japan (AG); Departments of Clinical Research (YM) and Epidemiology and Prevention (KK, AN, TM), National Center for Global Health and Medicine, Tokyo, Japan; Department of Internal Medicine, Mitsui Memorial Hospital, Tokyo, Japan (AI); Division of Diabetes and Metabolism, Iwate Medical University School of Medicine, Iwate, Japan (YT); Department of Health Promotion, National Institute of Public Health, Saitama, Japan (SO); Department of Public Health Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan (KY); Department of Public Health, Fujita Health University, Aichi, Japan (HY); Department of Basic Nursing and Health Science, Ehime University Graduate School of Medicine, Ehime, Japan (IS); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (YK); Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan (NS, ST); AXA Department of Health and Human Security (MI) and Diabetes and Metabolic Diseases (TK), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Public Health, Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (HI).
                Author notes
                Correspondence: Mitsuhiko Noda, Department of Diabetes Research, Diabetes Research Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan (e-mail: mnoda@ 123456hosp.ncgm.go.jp ).
                Article
                Accession ID: 00785
                DOI: 10.1097/MD.0000000000000785
                PMC ID: 4603057
                PubMed ID: 25929925
                SO-VID: 69f6d99c-cf15-4a97-81b3-000b11c8a8b2
                Copyright © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
                License:

                This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Date received : 8 January 2015
                Date revision received : 13 February 2015
                Date accepted : 25 March 2015
                Categories
                Subject: 3400
                Subject: Article
                Subject: Observational Study
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