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Original Investigation |

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

JAMA. 2014;311(12):1225-1233. doi:10.1001/jama.2014.1873.
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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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Figure 1.
Hazard Ratios for Incident Cardiovascular Disease (CVD) Outcomes by Baseline Levels of Glycemia Measures

Analyses were adjusted for age, smoking status, systolic blood pressure, total cholesterol level, and high-density lipoprotein cholesterol level and stratified by sex and trial group where appropriate. Participants were classified into groups of (1) HbA1c% (mmol/mol): <4.5 (<25.7), 4.5 to <5 (25.7-<31.1), 5 to <5.5 (31.1-<36.3) [reference category], 5.5 to <6 (36.6-<42.1), 6 to <6.5 (42.1-<48.0), and ≥6.5 (≥48.0); (2) fasting glucose (mg/dL): <76, 76 to <90, 90 to <105 [reference category], 105 to <119, 119 to <133, ≥133; (3) random glucose (mg/dL) <68, 68 to <90, 90 to <112 [reference category], 112 to <133, 133 to <155, ≥155; (4) Postload glucose (mg/dL): <68, 68 to <108, 108 to <148 [reference category], 148 to <187, 187 to <227, ≥227. These categories approximately correspond to 1-SD increments for each factor. Incident CVD outcomes refer to first-onset CVD cases, defined as fatal or nonfatal coronary heart disease or any stroke. SI conversion factors: To convert glucose values to mmol/L, multiply by 0.0555. Sizes of boxes are proportional to the inverse of the variance.

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Figure 2.
Hazard Ratios for Incident Cardiovascular Disease for Glycemia Measures by Selected Study-Level Characteristics

Participants with levels of glycemia measures below the mean were excluded. Baseline SD was used to calculate per-SD hazard ratio (HR). Analyses were conducted using studies with information across all levels of each subgroup variable. DCCT indicates Diabetes Control and Complications Trial; HPLC, high-performance liquid chromatography; ITA, immunoturbidimetric assay. A full list of the characteristics examined for heterogeneity is provided in eFigures 5 through 8 in Supplement.

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Figure 3.
Changes in Cardiovascular Disease Risk Discrimination After the Addition of Information on Glycemia Measures to Conventional Risk Factors

Incident cardiovascular disease outcomes refer to first-onset cardiovascular disease cases, defined as fatal or nonfatal coronary heart disease event or any stroke. Studies with missing self-reported diabetes information were excluded.aConventional risk factors include age, sex (stratified), smoking status, systolic blood pressure, and levels of total cholesterol and high-density lipoprotein cholesterol.bP < .05cP < .001.

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