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      Haemoglobin A1c even within non-diabetic level is a predictor of cardiovascular disease in a general Japanese population: the Hisayama Study

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          Abstract

          Background

          There is little information about predictive ability of haemoglobin A1c (HbA1c) for cardiovascular disease (CVD) in Asians. To investigate the discriminatory ability of HbA1c to identify subjects who are at greater risk of developing CVD in a prospective study of a defined community-dwelling Japanese population.

          Methods

          A total of 2,851 subjects aged 40–79 years were stratified into five groups (HbA1c levels with ≤ 5.0, 5.1–5.4, 5.5–6.4, and ≥ 6.5% and a group with antidiabetic medication) and followed up prospectively for 7 years (2002–2009).

          Results

          During the follow-up, 119 subjects developed CVD. The multivariable-adjusted risk of CVD was significantly increased in subjects with HbA1c levels of 5.5–6.4 and ≥ 6.5% and diabetic medication compared to HbA1c level with ≤ 5.0% (hazard ratio, 2.26 [95% confidence interval, 1.29–3.95] for the 5.5–6.4%; 4.43 [2.09–9.37] for the ≥ 6.5%; and 5.15 [2.65–10.0] for the antidiabetic medication group). With regard to CVD subtype, the positive associations between HbA1c levels and the risk of coronary heart disease (CHD) and ischaemic stroke were also significant, but no such associations were seen for haemorrhagic stroke. The C statistic for developing CVD was significantly increased by adding HbA1c values to the model including other risk factors (0.789 vs. 0762, p = 0.006), and the net reclassification improvement was 0.105 (p = 0.004).

          Conclusions

          Our findings suggest that elevated HbA1c levels are an independent risk factor for CVD, especially CHD and ischaemic stroke, and that the addition of HbA1c to the model with traditional risk factors significantly improves the predictive ability of CVD.

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          Most cited references30

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          Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study.

          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.

            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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              Short-term variability in measures of glycemia and implications for the classification of diabetes.

              Short-term variability in measures of glycemia has important implications for the diagnosis of diabetes mellitus and the conduct and interpretation of epidemiologic studies. Our objectives were to characterize the within-person variability in fasting glucose, 2-hour glucose, and hemoglobin A1c (HbA1c) levels and to assess the impact of using repeated measurements for classification of diabetes. We analyzed repeated measurements from 685 fasting participants without diagnosed diabetes from the National Health and Nutrition Examination Survey III Second Examination, a substudy conducted from 1988 to 1994 in which repeated examinations were conducted approximately 2 weeks after the original examination. Two-hour glucose levels had substantially more variability (within-person coefficient of variation [CV(w)], 16.7%; 95% confidence interval [CI], 15.0 to 18.3) compared with either fasting glucose (CV(w), 5.7%; 95% CI, 5.3 to 6.1) or HbA1c (CV(w,) 3.6%; 95% CI, 3.2 to 4.0) levels. The proportion of persons with a fasting glucose level of 126 mg/dL or higher (to convert to millimoles per liter, multiply by 0.0555) on the first test who also had a second glucose level of 126 mg/dL or higher was 70.4% (95% CI, 49.8% to 86.2%). Results were similar using the 2-hour glucose cutoff point of 140 mg/dL or higher. The prevalence of undiagnosed diabetes using a single fasting glucose level of 126 mg/dL or higher was 3.7%. If a second fasting glucose level of 126 mg/dL or higher was used to confirm the diagnosis (American Diabetes Association guidelines), the prevalence decreased to 2.8% (95% CI, 1.5% to 4.0%), a 24.4% decrease. We found high variability in 2-hour glucose levels relative to fasting glucose levels and high variability in both of these relative to HbA1c levels. Our findings suggest that studies that strictly apply guidelines for the diagnosis of diabetes (2 glucose measurements) may arrive at substantially different prevalence estimates compared with studies that use only a single measurement.
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                Author and article information

                Contributors
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central
                1475-2840
                2013
                7 November 2013
                : 12
                : 164
                Affiliations
                [1 ]Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka City 812-8582, Japan
                [2 ]Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
                Article
                1475-2840-12-164
                10.1186/1475-2840-12-164
                4176981
                24195452
                5223bbb2-04a2-4c1e-9398-cc1c3c3dacdc
                Copyright © 2013 Ikeda et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 August 2013
                : 5 November 2013
                Categories
                Original Investigation

                Endocrinology & Diabetes
                haemoglobin a1c,cardiovascular disease,risk factor,prospective cohort study,epidemiology

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