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Background-Hemoglobin A1c (HbA1c), a time-integrated marker of glycemic control, predicts risk of coronary heart disease
(CHD) among diabetics. Few studies have examined HbA1c and risk of CHD among women and men without clinically elevated
levels or previously diagnosed diabetes.
Methods and Results-We conducted parallel nested casecontrol studies among women (Nurses Health Study) and men (Health
Professionals Follow-up Study). During 14 and 10 years of follow-up, 468 women and 454 men developed incident nonfatal
myocardial infarction (MI) and fatal CHD. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these
analyses, participants with a history of diabetes or HbA1c levels 6.5% at baseline were excluded. Compared with HbA1c of 5.0% to
<5.5%, those with an HbA1c of 6.0% to <6.5% had a multivariable-adjusted relative risk (RR) of CHD of 1.90 (95% CI 1.11 to 3.25) in
women and 1.81 (95% CI 1.09 to 3.03) in men. The pooled RR of CHD was 1.29 (95% CI 1.11 to 1.50) for every 0.5%-increment
increase in HbA1c levels and 1.67 (95% CI 1.23 to 2.25) for every 1%-increment increase, with the risk plateauing around 5.0%.
Furthermore, participants with HbA1c levels between 6.0% and <6.5% and C-reactive protein levels >3.0 mg/L had a 2.5-fold higher
risk of CHD compared with participants in the lowest categories of both biomarkers.
Conclusions-Our ndings suggest that HbA1c is associated with CHD risk among apparently healthy, nondiabetic women and
men and may be an important early clinical marker of disease risk. ( J Am Heart Assoc. 2013;2:e000077 doi: 10.1161/
JAHA.112.000077)
Key Words: coronary heart disease C-reactive protein epidemiology glycated hemoglobin inammation
DOI: 10.1161/JAHA.112.000077
Pai et al
Methods
Study Population
Assessment of CHD
MI was conrmed by study physicians blinded to participants
exposure status if it met World Health Organization criteria
(symptoms plus either diagnostic electrocardiographic
changes or elevated levels of cardiac enzymes).17,18 Deaths
were identied from state vital records and the National
DOI: 10.1161/JAHA.112.000077
ORIGINAL RESEARCH
Pai et al
Statistical Analyses
We analyzed the 2 cohorts separately. HbA1c levels were
categorized into quintiles based on the sex-specic distributions among the controls as well as according to categories
(<5.0%, 5.0% to <5.5%, 5.5% to <6.0%, and 6.0% to <6.5%). In
the categorical analyses, the HbA1c 5.0% to <5.5% category
was used as the reference because there were more
participants than in the <5.0% category. Because of this study
design, the odds ratio derived from the logistic regression
directly estimates the incidence rate (hazard) ratio and, thus,
the RR.16,23 We analyzed the association between HbA1c levels
and risk of CHD using both conditional and unconditional
logistic regression with adjustment for matching factors and
laboratory batch. Because both analyses provided essentially
the same results, we present unconditional logistic regression,
which parallels the subgroup analyses. In our multivariable
model, we further adjusted for parental history of MI before the
age of 60 (yes/no), alcohol intake (nondrinker; 0.1 to 4.9, 5.0
to 14.9, 15.0 to 29.9, or 30.0 g/d; or missing), physical
activity (quintiles), total cholesterol:HDL cholesterol ratio
(quintiles), BMI in categories (<20, 20 to 24.9, 25 to 29.9,
30 to 34.9, and 35 kg/m2), and postmenopausal hormone
therapy (yes/no, women only). Additional adjustment for
hypertension (yes/no) at baseline, triglyceride levels (quintiles), and CRP levels (quintiles) was also conducted. Correlation coefcients were calculated using age-adjusted
Spearman partial correlation coefcients. To test for linear
trend, we used the median HbA1c levels in the control
categories as a continuous variable. In addition, we conducted
analyses per 0.5%-increment increase in HbA1c levels. We
examined the possibly nonlinear relation between HbA1c and
CHD nonparametrically with restricted cubic splines.24 Tests
for nonlinearity used the likelihood ratio test, comparing the
model with only the linear term to the model with the linear
and the cubic spline terms. To pool the RR estimates for men
and women, we used the weighted average of estimates using
the DerSimonian and Laird random effects model.25 Because
we are using a single measure of HbA1c to predict future
disease over long-term follow-up, uctuations in baseline
biological risk factors over time may lead to an underestimation of the true association in the form of regression dilution
bias.26,27 To account for potential changes in our baseline
DOI: 10.1161/JAHA.112.000077
Results
Cardiovascular risk factors were higher or more frequent
among the cases compared with the controls in both men and
women (Table 1). As expected, cases were more likely to have
parental history of early MI, history of hypercholesterolemia,
and history of hypertension. Also, cases were more likely to
have higher CRP levels and adverse lipid proles compared
with controls for both women and men. Age-adjusted
Spearman partial correlation coefcients are presented
among controls for women and men (Table 2). HbA1c
percentage was positively correlated with CRP levels, triglycerides:HDL cholesterol ratio, triglycerides, and BMI and
inversely correlated with HDL cholesterol and alcohol intake.
Among participants with HbA1c levels <6.5% and without
history of diabetes at baseline, greater HbA1c levels were
signicantly associated with an increased risk of CHD in both
women and men. Comparing extreme quintiles of HbA1c
levels, the multivariable-adjusted RR of CHD was 1.70 (95% CI
1.22 to 2.36) in the pooled analysis, with a P for trend of
<0.001 (Table 3). Because additional adjustment for history
of hypertension, triglycerides, and CRP levels did not significantly attenuate the risk estimates, we refer to model 3 in
multivariable-adjusted and pooled analyses in Table 3.
We further examined the association using xed cut points.
Compared with HbA1c category 5.0% to <5.5% (reference), the
pooled multivariable-adjusted RRs for CHD were 1.14 (95% CI
0.82 to 1.59) for <5.0%, 1.34 (95% CI 1.08 to 1.68) for 5.5% to
<6.0%, and 1.85 (95% CI 1.28 to 2.69) for 6.0% to <6.5%
(Figure 1). A signicantly elevated risk of CHD was observed
among nondiabetic women and men with HbA1c levels of
5.5%. Even in these populations restricted to lower HbA1c
levels, we found that for every 0.5%-increment increase in
HbA1c levels, the RR of CHD was 1.32 (95% CI 1.05 to 1.65) in
women and 1.27 (95% CI 1.04 to 1.55) in men, and 1.29 (95%
CI 1.11 to 1.50) when pooled. This association did not differ
by health and lifestyle factors such as age, smoking status,
BMI <25 and 25 kg/m2, history of hypertension, or parental
history of early MI (Table S1). We further examined the joint
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Pai et al
Cases
Controls
371
832
Age, y
59.96.6
59.76.5
Current smokers, %
28.3
26.7
25.84.7
24.94.1
43.0
Characteristics
P Value
P Value
Cases
Controls
396
843
64.18.8
64.08.6
9.6
9.1
0.004
25.93.1
25.63.3
0.10
45.3
0.76
24.5
13.9
<0.001
15.9
11.4
0.03
History of hypercholesterolemia, %
52.3
39.2
<0.001
50.0
41.2
0.004
History of hypertension, %
44.7
25.4
<0.001
34.3
28.5
0.04
NSAID use, %
67.7
69.1
0.62
46.7
43.5
0.29
1796561
1765510
0.37
2076645
2044642
0.41
0.09
0.02
0.69
0.08
HbA1c, %
0.01
0.01
CRP, mg/L
<0.001
<0.001
23540.7
22740.8
0.001
21238.3
20436.2
<0.001
54.014.8
60.916.7
<0.001
42.911.5
46.412.7
<0.001
14637.0
13537.5
<0.001
13534.3
12731.0
<0.001
Triglycerides, mg/dL
<0.001
<0.001
4.661.5
4.001.3
<0.001
5.191.3
4.661.3
<0.001
MET-h indicates metabolic equivalent hours; HbA1c, hemoglobin A1c; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
*Matching criteria were age, smoking status, and date of blood draw; in women, additional matching criteria included fasting status.
Values are meanSD for continuous variables and proportions for categorical variables, except HbA1c, CRP, triglycerides, alcohol, and physical activity, which are shown as median
(interquartile range).
P for difference between cases and controls (unadjusted), determined by Student t test for rows with means, by Wilcoxons rank sum test for rows with medians, and by v2 test for rows
with proportions.
effect of CRP levels based on clinical cut points for CRP and
categories of HbA1c. Of note, in the lower risk group with CRP
levels 3.0 mg/L, a 0.5%-increment increase of HbA1c was
signicantly associated with risk of incident CHD among
women (RR 1.42, 95% CI 1.04 to 1.94) and men (RR 1.28, 95%
CI 1.03 to 1.60). In pooled analyses, participants in the
highest CRP and HbA1c categories had an RR of CHD of 2.49
(95% CI 1.32 to 4.71) compared with participants in the
lowest of both biomarkers (Figure 2).
A single biomarker at baseline may be a better proxy for
exposure over the rst several years and possibly become
less correlated with exposure over a longer period. When we
stratied according to the midpoint of follow-up, the association was strongest among cases and controls in the rst
7 years of follow-up. For every 0.5%-increment increase in
HbA1c levels in the earlier follow-up (<7 years) only, the
multivariable-adjusted RR of incident CHD was 1.39 (95% CI
DOI: 10.1161/JAHA.112.000077
0.97 to 1.98) for women, 1.33 (95% CI 1.02 to 1.73) for men,
and 1.35 (95% CI 1.09 to 1.67) when we pooled the
estimates. In the later follow-up (7 years) only, the corresponding RRs were 1.17 (95% CI 0.90 to 1.52) for women,
1.26 (95% CI 0.92 to 1.72) for men, and 1.20 (95% CI 0.98 to
1.47) when pooled. Finally, when we controlled for regression
dilution bias to account for variability in the baseline measure,
the pooled RR per 0.5% increment was 1.51 (95% CI 1.13 to
2.02) when restricted to the earlier follow-up cycle and 1.42
(95% CI 1.16 to 1.74) for the entire follow-up cycle.
Discussion
In these prospective nested casecontrol studies in 2 cohorts
of US health professionals, we found that HbA1c was
predictive of CHD risk in participants without diagnosed
Journal of the American Heart Association
ORIGINAL RESEARCH
Table 1. Baseline Characteristics of Subjects With Incident Myocardial Infarction (Cases) and Matched* Event-Free Controls
Among Women (the Nurses Health Study, 14 Years of Follow-up) and Men (the Health Professionals Follow-Up Study, 10 Years of
Follow-up) Without History of Diabetes and Hemoglobin A1c <6.5%
Pai et al
HbA1c%
NHS
HPFS
CRP
0.15
0.13
Total cholesterol
0.04
0.08*
LDL cholesterol
0.04
0.09
HDL cholesterol
0.05
0.08*
0.09
0.11
Triglycerides
0.07*
0.12
BMI
0.09
0.10
Alcohol, g/d
0.03
0.08*
HbA1c indicates hemoglobin A1c; NHS, Nurses Health Study; HPFS, Health Professionals
Follow-Up Study; CRP, C-reactive protein; LDL, low-density lipoprotein; HDL, high-density
lipoprotein; BMI, body mass index.
*P<0.05, P<0.01, P<0.001.
Table 3. Estimated Relative Risks (and 95% CIs) of Myocardial Infarction During Follow-up According to Quintiles of Baseline
Percent Hemoglobin A1c Among Women (Nurses Health Study, 14 Years of Follow-up) and Men (the Health Professionals
Follow-Up Study, 10 Years of Follow-up)
Quintile of HbA1c*
1
P Trend
<5.1
5.1 to <5.3
5.3 to <5.5
5.5 to <5.7
5.7
Cases/controls
62/166
61/168
75/165
84/167
89/166
Model 1
1.0
<0.001
Model 2
1.0
0.009
1.0
0.01
1.0
0.02
5.4 to <5.6
5.6 to <5.8
5.8
Model 3
Model 4
<5.2
5.2 to <5.4
Cases/controls
64/168
66/169
87/168
73/170
106/168
Model 1
1.0
0.001
1.0
0.03
1.0
0.02
1.0
0.02
126/334
127/337
162/333
157/337
195/334
1.0
Model 2
Model 3
Model 4
Pooled
Cases/controls
Model 3
<0.001
HbA1c indicates hemoglobin A1c; NHS, Nurses Health Study; HDL, high-density lipoprotein; CRP, C-reactive protein.
*Quintiles of HbA1c are based on controls in each sex.
P for trend based on median HbA1c levels in quintiles of the control subjects.
Adjusted for age, smoking status, date of blood drawing, fasting status (in NHS only), and laboratory batch.
Additionally adjusted for family history of myocardial infarction before age of 60 years, alcohol intake, physical activity, nonsteroidal antiinammatory drug use, total cholesterol:HDL
cholesterol ratio, and hormone replacement therapy use among women.
DOI: 10.1161/JAHA.112.000077
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ORIGINAL RESEARCH
Pai et al
DOI: 10.1161/JAHA.112.000077
Sources of Funding
This study was supported by grants (HL35464, CA55075,
HL34594, CA87969, and CA49449) from the National Institutes of Health. Dr Pai was supported in part by National
Institutes of Health grant HL088372. The content is solely the
responsibility of the authors and does not necessarily
represent the ofcial views of the National Institutes of Health.
Disclosures
None.
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Hemoglobin A1c Is Associated With Increased Risk of Incident Coronary Heart Disease Among
Apparently Healthy, Nondiabetic Men and Women
Jennifer K. Pai, Leah E. Cahill, Frank B. Hu, Kathryn M. Rexrode, JoAnn E. Manson and Eric B.
Rimm
J Am Heart Assoc. 2013;2:e000077; originally published March 22, 2013;
doi: 10.1161/JAHA.112.000077
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