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Haemoglobin A1c concentrations were associated with increased cardiovascular disease and all cause mortality
  1. Ronald J Sigal, MD
  1. Ottawa Health Research Institute and University of Ottawa
 Ottawa, Ontario, Canada

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 Q What is the relation between haemoglobin (Hb) A1c concentrations and coronary heart disease (CHD) events, cardiovascular disease (CVD) events, and all cause mortality?

    Clinical impact ratings GP/FP/Primary care ★★★★★★☆ IM/Ambulatory care ★★★★★☆☆ Cardiology ★★★★★★☆ Endocrine ★★★★★☆☆


    Embedded ImageDesign:

    cohort study (European Prospective Investigation into Cancer in Norfolk [EPIC-Norfolk]) with a mean follow up of 6 years.

    Embedded ImageSetting:

    Norfolk, UK.

    Embedded ImagePatients:

    10 232 patients 45–79 years of age (54% women, 2.4% with diabetes) who were recruited from general practice registers and had baseline data on a health and lifestyle questionnaire and HbA1c concentrations.

    Embedded ImageRisk factors:

    HbA1c concentrations, known diabetes, age, body mass index, waist-to-hip ratio, systolic blood pressure, cholesterol concentrations, triglyceride concentrations, cigarette smoking, and history of heart attack or stroke.

    Embedded ImageOutcomes:

    CHD events (hospital admission or death from CHD), CVD events (hospital admission or death from CHD, stroke, or other vascular causes), and all cause mortality.


    Persons with known or undiagnosed diabetes had a greater risk of all cause mortality and CVD or CHD events than those without diabetes. A gradient of increasing rates of all cause mortality, CHD, and CVD was found for the entire distribution of HbA1c concentrations in men and women (p<0.001 for linear trend).

    Regression analyses adjusted for age and other risk factors (except for HbA1c concentration) showed that compared with persons without diabetes, men with diabetes had a higher risk of CHD events, CVD events, and all cause mortality, and women with diabetes had an increased risk of CHD events and CVD events (table). In a regression analysis that did not adjust for diabetes, HbA1c concentrations predicted an increased risk of CHD, CVD, and all cause mortality in both men and women. A 1% increase in HbA1c concentration was associated with a 20–30% increase in event rates. When the regression model included both diabetes and HbA1c concentrations, similar relative risks for an increase in HBA1c were noted, but diabetes was no longer a significant risk factor.

    Adjusted relative risks (RRs) for coronary heart disease events, cardiovascular disease events, and all cause mortality by haemoglobin A1c concentrations and history of diabetes*


    A 1% increase in haemoglobin A1c concentrations was associated with a 20–30% increase in cardiovascular events and all cause mortality in men and women 45–79 years of age. This relation was independent of diabetes status.

    Abstract and commentary also appear in ACP Journal Club


    Diabetes mellitus is a major risk factor of CVD, and unlike hypertension, smoking, and dyslipidaemia, it is becoming more common over time.

    The diagnostic criteria for diabetes include fasting plasma glucose concentrations ⩾7.0 mmol/l or 2 hour postload plasma glucose concentrations ⩾11.1 mmol/l, values above which the risk of microvascular complications of diabetes, such as retinopathy, neuropathy, and nephropathy, increases. These values correspond approximately to an HbA1c concentration of 7%. However, there is considerable epidemiological evidence that the risk of CVD begins to increase at lower glycaemic concentrations than would be considered “abnormal”—levels that would not be associated with increased microvascular disease risk.1 The study by Khaw et al adds to this evidence because of its large study population and particularly large number of female participants.

    In this study, 72% of the excess CVD risk that was attributable to higher HbA1c concentrations occurred in patients with HbA1c concentrations of 5.0–6.9%. In light of this evidence, perhaps the cut point for a “normal” HbA1c concentration should be revised downward, as has been done for cholesterol and blood pressure. It would also be desirable to develop and validate cardiovascular risk calculators that include HbA1c concentration as a predictor variable, as has been done for patients with type 2 diabetes in the UKPDS Risk Engine.2 In the meantime, HbA1c concentrations provide an additional measure of an individual patient’s CVD risk.


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    • For correspondence: Dr K T Khaw, University of Cambridge, Cambridge, UK.

    • Sources of funding: Medical Research Council United Kingdom; Cancer Research United Kingdom; European Union; Stroke Association; British Heart Foundation.