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Journal of the American College of Cardiology
© 2004 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 43, No. 12, 2004
ISSN 0735-1097/04/$30.00
doi:10.1016/j.jacc.2003.10.074
Heart Failure
The Association of Fasting Glucose Levels With
Congestive Heart Failure in Diabetic Adults ⱖ65 Years
The Cardiovascular Health Study
Joshua I. Barzilay, MD,* Richard A. Kronmal, PHD,† John S. Gottdiener, MD,§
Nicholas L. Smith, PHD, MPH,‡ Gregory L. Burke, MD, MS,㛳 Russell Tracy, PHD,¶
Peter J. Savage, MD,# Michelle Carlson, PHD**
Atlanta, Georgia; Seattle, Washington; Roslyn, New York; Winston-Salem, North Carolina; Colchester, Vermont;
and Bethesda and Baltimore, Maryland
The purpose of this study was to determine if fasting glucose levels are an independent risk
factor for congestive heart failure (CHF) in elderly individuals with diabetes mellitus (DM)
with or without coronary heart disease (CHD).
BACKGROUND Diabetes mellitus and CHF frequently coexist in the elderly. It is not clear whether fasting
glucose levels in the setting of DM are a risk factor for incident CHF in the elderly.
METHODS
A cohort of 829 diabetic participants, age ⱖ65 years, without prevalent CHF, was followed
for five to eight years. The Cox proportional hazards modeling was used to determine the risk
of CHF by fasting glucose levels. The cohort was categorized by the presence or absence of
prevalent CHD.
RESULTS
For a 1 standard deviation (60.6 mg/dl) increase in fasting glucose, the adjusted hazard ratios
for incident CHF among participants without CHD at baseline, with or without an incident
myocardial infarction (MI) or CHD event on follow-up, was 1.41 (95% confidence interval
1.24 to 1.61; p ⬍ 0.0001). Among those with prevalent CHD at baseline, with or without
another incident MI or CHD event on follow-up, the corresponding adjusted hazard ratio
was 1.27 (95% confidence interval 1.02 to 1.58; p ⬍ 0.05).
CONCLUSIONS Among older adults with DM, elevated fasting glucose levels are a risk factor for incident
CHF. The relationship of fasting glucose to CHF differs somewhat by the presence or
absence of prevalent CHD. (J Am Coll Cardiol 2004;43:2236 – 41) © 2004 by the
American College of Cardiology Foundation
OBJECTIVES
Congestive heart failure (CHF) and diabetes mellitus (DM)
are age-related disorders that frequently coexist (1,2). Despite their close association, there is uncertainty whether
elevated glucose levels are a risk factor for CHF. Cohort
(3–7) and clinic (8 –11) studies of people with DM have
reached conflicting results. In a recent analysis of the
diabetic and nondiabetic cohorts of the Cardiovascular
Health Study (CHS)—a longitudinal study of elderly adults
whose purpose is to identify factors related to the onset and
course of cardiovascular disease and stroke—we found that
a history of DM predicted CHF, but not a glucose level
⬎125 mg/dl (12). The uncertainty regarding the association
of elevated glucose levels and incident CHF may stem from
the fact that CHF is a heterogeneous disorder. It may occur
as a result of myocardial damage secondary to coronary heart
disease (CHD), but may also occur in the absence of CHD
due to myocardial dysfunction. If elevated glucose levels
have a differing degree of association with these conditions,
then the relationship of elevated glucose levels to CHF risk
would vary as well.
In the present study, we examine the diabetic cohort of
CHS to determine the role of fasting glucose levels for
incident CHF in those with and without CHD at baseline
or on follow-up.
METHODS
From the *Kaiser Permanente of Georgia and the Division of Endocrinology,
Emory University School of Medicine, Atlanta, Georgia; †Department of Biostatistics and ‡Department of Epidemiology, University of Washington, Seattle, Washington; §Department of Cardiology, St. Francis Hospital, Roslyn, New York;
㛳Department of Public Health Sciences, Wake Forest University School of Medicine,
Winston-Salem, North Carolina; ¶Department of Pathology, University of Vermont
College of Medicine, Colchester, Vermont; #Division of Epidemiology and Clinical
Applications, National Heart, Lung, Blood Institute, National Institutes of Health,
Bethesda, Maryland; and the **Center on Aging and Health, Johns Hopkins School
of Public Health, Baltimore, Maryland. Supported by contracts NO1-HC-85079
through NO1-HC-85086, NO1-HC-35129, and NO1-HC-15103 from the National Heart, Lung, and Blood Institute.
Manuscript received July 29, 2003; revised manuscript received October 15, 2003,
accepted October 20, 2003.
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Recruitment methods for CHS have been published (13). In
brief, a random sample of individuals, ⱖ65 years of age,
derived from Medicare eligibility lists, and other household
members ⱖ65 years, were invited to participate in the study.
Potential participants were excluded if they had illnesses
that were expected to lead to early death. A total of 5,201
participants were recruited in 1989 to 1990 (called the
original cohort), and 687 were recruited in 1992 to 1993 to
provide additional representation of African Americans
(called the new cohort). For these analyses, only participants
JACC Vol. 43, No. 12, 2004
June 16, 2004:2236–41
Abbreviations and Acronyms
CHD ⫽ coronary heart disease
CHF ⫽ congestive heart failure
CHS ⫽ Cardiovascular Health Study
DM ⫽ diabetes mellitus
LV ⫽ left ventricle/ventricular
MI ⫽ myocardial infarction
with DM at entry were studied (n ⫽ 910). All participants
signed informed consent.
Upon entry into the study, participants were invited for a
baseline interview. Information on prescription medications
used in the preceding two weeks (including insulin and oral
hypoglycemic agents) was collected (14). During a subsequent clinic visit, venipuncture was done after an overnight
fast. Plasma and serum were frozen at ⫺70°C, and shipped
to the CHS Central Laboratory (University of Vermont,
Burlington, Vermont). Fasting serum chemistry analyses
were performed (15). Glucose levels were measured on a
Kodak Ektachem 700 Analyzer (Ektachem Test Methodologies, Eastman Kodak, Rochester, New York, March
1985) and assayed within 30 days. Average monthly coefficient of variation was 0.93%. One year after the baseline
examination, a subset of CHS participants had a hemoglobin A1c test performed as part of a substudy.
Echocardiograms were obtained during the baseline examination for 99.1% of the original cohort in 1989 to 1990.
Echocardiograms for the African-American participants
were obtained in 1994 to 1995, one year after enrollment in
the study. Therefore, these latter echocardiograms are not
used in this analysis because some incident events may have
occurred before performing the echocardiogram. Moreover,
laboratory values, medication use, and anthropometric measurements would have differed from the baseline examination to the time that the echocardiogram was performed.
For those with incident CHF, left ventricular (LV) systolic
function data was obtained in many (but not all) cases from
echocardiographic reports at the point of care during index
hospitalization or office visit at which the clinical diagnosis
of CHF was made. The reports were reviewed by CHS
investigators.
Definitions. Diabetes mellitus was defined by a fasting
glucose ⱖ126 mg/dl or the use of antidiabetic agents.
Self-report of DM was not a defining criterion. Subjects
who were not fasting at blood draw or whose diabetic status
could not be determined from medication lists were excluded (n ⫽ 64).
Baseline and incident CHD was defined as a history of
myocardial infarction (MI) or a non-MI event, such as
angina pectoris, or a revascularization procedure (coronary
artery bypass grafting or percutaneous transluminal coronary
angioplasty).
Global LV function was qualitatively assessed from the
baseline two-dimensional echocardiogram as normal, borderline, or abnormal ejection fraction. Inter-reader agree-
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Barzilay et al.
Fasting Glucose and CHF in Elderly Patients With DM
2237
ment was 94%, and intra-reader agreement was 98% of
paired studies (16). Qualitatively assessed normal LV function on the echocardiogram corresponded to an ejection
fraction ⱖ55%, borderline was 45% to 54%, abnormal was
⬍45%.
The diagnosis of incident CHF was based on data from
an index hospitalization, outpatient visits for CHF, or
self-report of a physician diagnosis of CHF (17). These
reports were confirmed by documentation in the participant’s medical records of a constellation of symptoms
(dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea) and physical signs (edema, pulmonary rales, gallop
rhythm, displaced LV apical impulse), and by supporting
clinical findings such as chest X-ray and medications
(digoxin, hydralazine, or loop diuretics). Supporting clinical
findings were adjudicated by the CHS events committee,
which classified all cardiovascular events (17).
Analyses for this study are based on events through June
1998. Follow-up was ⬎95% complete for the original and
the African-American cohorts based on telephone contact
and review of Medicare data tapes.
Statistical methods. Baseline characteristics of the cohort,
categorized by development of CHF, were compared using
the chi-square test for discrete values and the t test for
continuous data. The Cox proportional hazards models
were used to examine the effect of fasting glucose levels on
incident CHF. A fasting glucose of 200 mg/dl was approximately the 80th percentile of this cohort. Models were
generated in stages. Demographic, laboratory, and clinical
measures were taken first. Once significant predictors were
identified, time-dependent variables (new MI or non-MI
CHD event) were added to each model to evaluate the risk
of these events on CHF. To determine the risk associated
with fasting glucose in those without baseline CHD or an
incident MI/other CHD event before the occurrence of
incident CHF, significant interactions of risk factors and
time-dependent variables were included in the model. At
each stage, stepwise selection was used with a value of p ⬍
0.05. All analyses were done using SPSS Version 11.0
(SPSS Inc., Chicago, Illinois).
RESULTS
There were 910 participants in CHS with DM at baseline
(15.5% of the two cohorts combined). Of these, 81 (8.9%)
had prevalent CHF and were not considered in this analysis.
Of the remaining 829 participants, there were 626 without
clinical CHD and 203 with clinical CHD at baseline
(Fig. 1).
Incident CHF in those without baseline CHD. There
were 123 incident CHF events among the 626 individuals
without CHD at baseline—55 after an incident CHD/MI
event, and 68 without an incident CHD/MI event. Baseline
characteristics of these 626 participants, categorized by
development or absence of incident CHF, are shown in
Table 1. Those who developed CHF were older, more
2238
Barzilay et al.
Fasting Glucose and CHF in Elderly Patients With DM
JACC Vol. 43, No. 12, 2004
June 16, 2004:2236–41
Table 2. Incidence Rates of CHF in 1,000 Person-Years for
Those Without Prevalent CHD at Baseline Categorized by
Quartiles of Fasting Glucose Levels
Figure 1. Incident congestive heart failure (CHF) in the diabetic cohort of
the Cardiovascular Health Study (CHS) categorized by the absence or
presence of coronary heart disease (CHD). MI ⫽ myocardial infarction.
centrally obese, and had higher systolic blood pressure,
fasting glucose, uric acid, and C-reactive protein levels than
those who did not develop CHF. They did not differ
significantly with respect to LV function at baseline or
hypoglycemic medication use. Systolic LV function at
baseline was usually normal. At the time of hospitalization
for the incident CHF, LV function was preserved in more
than one-half of cases (among those with no MI or CHD
event before CHF, 14 of 32 [43.8%] had abnormal ejection
Glucose
Quartile*
n
Incident
CHF Events
Incidence
Rate
I
II
III
IV
158
153
157
158
18
32
29
44
17.7
31.8
28.8
47.7
*Quartiles of fasting glucose (mg/dl): I ⫽ 61 to 132; II ⫽ 133 to 152; III ⫽ 153 to
190; IV ⫽ 191 to 657.
CHF ⫽ congestive heart failure; CHD ⫽ coronary heart disease; n ⫽ the number
in each quartile.
fraction; among those with MI or CHD event before CHF,
12 of 30 [40.0%] had abnormal ejection fraction).
The incident rate of CHF in the cohort was 31.1 cases
per 1,000 person-years. The rate in nondiabetic CHS
participants without baseline CHD was 12.7 cases per 1,000
person-years. The incidence rates of CHF events per 1,000
patient-years of follow-up by fasting glucose quartiles are
shown in Table 2. There was a near doubling of rate in the
2nd and 3rd quartiles as compared with the 1st quartile
(31.8 and 28.8 cases per 1,000 patient-years, respectively, vs.
17.7). There was a near tripling in rate in the 4th quartile
Table 1. Baseline Characteristics of the CHS Diabetic Cohort Without Clinical CHD at
Baseline Categorized by Incidence of CHF
Baseline Characteristic
Gender (% male)
Age (yrs)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
BMI (kg/m2)
Hip circumference (cm)
Waist circumference (cm)
Smoking (%)
Never
Former
Current
Diabetic medications (%)
None
OHGA
Insulin ⫾ OHGA
LV function at baseline (%)*
Normal (n ⫽ 477)
Borderline (n ⫽ 33)
Abnormal (n ⫽ 13)
LV function at hospitalization (%)†
Normal (n ⫽ 27)
Borderline (n ⫽ 9)
Abnormal (n ⫽ 26)
Fasting glucose (mg/dl)
Fasting insulin (uIU/ml)
Uric acid (mg/dl)
Creatinine (mg/dl)
C reactive protein (mg/l)
Albumin (mg/dl)
No CHF
n ⴝ 503
CHF
n ⴝ 123
45.9
72.6 (5.4)
140.6 (21.6)
71.8 (11.4)
28.5 (4.8)
104.7 (10.0)
100.1 (12.2)
48.0
73.7 (5.5)
148.5 (20.1)
73.0 (14.2)
29.2 (4.9)
107.8 (10.7)
103.2 (13.8)
49.3
39.8
10.9
42.3
44.7
13.0
53.7
29.6
16.7
42.3
36.6
21.1
92.4
5.2
2.4
86.3
10.8
2.9
166.6 (52.5)
30.0 (49.0)
5.7 (1.5)
1.0 (0.5)
4.7 (9.0)
4.0 (0.3)
43.5
14.5
42.0
190.0 (83.0)
38.1 (67.8)
6.0 (1.6)
1.1 (0.4)
6.8 (12.3)
4.0 (0.3)
p Value
0.03
⬍ 0.001
0.003
0.01
⬍ 0.001
0.03
0.03
*In those without an incident CHF event in the original cohort; †For those with incident CHF in the original cohort, 98 had
data available. Values are means and SD. Only statistically significant p values are shown.
BMI ⫽ body mass index; CHF ⫽ congestive heart failure; CHS ⫽ Cardiovascular Health Study; LV ⫽ left ventricle;
OHGA ⫽ oral hypoglycemic agents.
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Barzilay et al.
Fasting Glucose and CHF in Elderly Patients With DM
JACC Vol. 43, No. 12, 2004
June 16, 2004:2236–41
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Table 3. Cox Regression Models of the Association of Fasting Blood Glucose Level per 1 SD
Increase of Fasting Glucose (60.6 mg/dl) and as Quartiles of Fasting Glucose Levels on Incident
CHF Among Diabetic Participants in the CHS Without Baseline CHD
Fasting glucose increase
of 60.6 mg/dl
Fasting glucose quartiles
1st
2nd
3rd
4th
Model I
Model II*
Model III†
1.37 (1.21, 1.56)
1.41 (1.24, 1.62)
1.41 (1.24, 1.61)
1.00
1.81 (1.00, 3.28)
1.67 (0.92, 3.04)
2.91 (1.66, 5.09)
1.00
1.51 (0.83, 2.75)
1.80 (0.99, 3.30)
3.45 (1.94, 6.15)
1.00
1.73 (0.94, 3.20)
1.88 (1.02, 3.46)
3.64 (2.04, 6.49)
Continuous fasting glucose hazard ratios are in SD units of 60.6 mg/dl. Quartiles of fasting glucose (mg/dl): I ⫽ 61 to 132; II
⫽ 133 to 152; III ⫽ 153 to 190; IV ⫽ 191 to 657. *Adjusted for age, systolic blood pressure, C reactive protein level, uric acid
level, smoking status (never, former, present), body mass index, waist circumference, and oral hypoglycemic agents, and insulin
use (as compared with no treatment for diabetes mellitus i.e., newly diagnosed diabetes mellitus). All are statistically significant
predictors of congestive heart failure (CHF), except insulin use. †Adjusted for factors in model II plus incident myocardial
infarction and coronary heart disease (CHD) event before CHF. All are significant predictors of CHF other than insulin use.
CHS ⫽ Cardiovascular Health Study.
(47.7 cases per 1,000 patient-years) relative to the 1st
quartile.
Results of the Cox proportional hazards models examining the effect of fasting glucose on incident CHF risk are
shown in Table 3. In unadjusted analysis, a 1 standard
deviation increase in fasting glucose level (60.6 mg/dl) was
associated with a 37% increased risk of CHF (model I, p ⬍
0.0001). When adjustment was made for other baseline risk
factors, a further increase in association of fasting glucose
with incident CHF was found (model II, p ⬍ 0.0001).
Addition of time-dependent variables (incident MI or other
CHD event) did not change this association (model III, p ⬍
0.0001). A test for interaction between fasting glucose levels
and incident MI before incident CHF was not significant,
suggesting the effect of glucose on CHF did not differ by the
presence or absence of incident MI. Several other significant
interactions between incident MI and baseline variables had
little effect on the risk associated with fasting glucose levels
and CHF (data not shown). When analysis was repeated
with fasting glucose levels as quartiles, there was an increase
in risk from the first to the 2nd and 3rd quartiles. There was
a further increase in the 4th quartile. With adjustment for
baseline factors (model II) and incident MI and CHD
events (model III), the association of fasting glucose with
CHF increased, especially for those in the 4th quartile.
Incident CHF in those with baseline CHD. There were
203 participants at baseline without CHF who had clinical
CHD. Among them, 83 incident CHF events occurred for
a rate of 78.3 cases per 1,000 person-years. The rate in
nondiabetic CHS participants with baseline CHD was 30.9
cases per 1,000 person-years. Among those for whom
echocardiographic data was available at the time of the
CHF event, 12 of 21 (57.1%) had an abnormal ejection
fraction without an additional incident MI or CHD event,
and 7 of 15 (46.7%) had an abnormal ejection fraction with
an incident MI or CHD event.
In unadjusted analysis, a 1 standard deviation increase in
fasting glucose level (60.6 mg/dl) was associated with a 16%
increased risk of CHF (model I, p ⫽ 0.15) (Table 4). When
adjustment was made for other baseline risk factors, an
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increase in association was found (model II, p ⬍ 0.05).
Addition of time-dependent variables (incident MI or other
CHD event) did not significantly change this association
(model III, p ⬍ 0.05). When the analysis was repeated with
fasting glucose levels as quartiles, there was an increase in
risk for CHF in the 4th quartile relative to the other
quartiles, especially in models II and III.
Correlation coefficient. Of the 829 individuals in this
study, 136 had a hemoglobin A1c test done one year after
the baseline examination. The correlation coefficient between the baseline fasting glucose levels and percent hemoglobin A1c was 0.59 (p ⬍ 0.000001).
DISCUSSION
This study shows that fasting glucose levels are related to
CHF risk in older adults with DM. Among those without
prevalent CHD, our models show an ⬃40% increase in risk.
Among those with prevalent CHD, the risk of CHF
associated with elevated fasting glucose level is also present
but not as strong. The relationship, however, is not well
estimated because of the small number of participants in the
group.
Raised glucose levels may lead to CHF in the absence of
CHD by several mechanisms. Raised levels may reflect
poorer compliance with medications or poorer medical care.
In this study, however, the use of hypoglycemic agents was
the same in those who did or did not develop CHF. Second,
hyperglycemia impairs endothelial function and vasodilation, impeding the ability of coronary arteries to increase
myocardial blood flow (18). Finally, elevated glucose levels
may have a deleterious effect on the myocardium leading to
fibrosis and stiffness (19 –23) with diminished diastolic
filling. Diastolic dysfunction has been described as a cause of
CHF in adults with DM (24). In CHS, most participants
with CHF had normal, or borderline, impairment of systolic
function, presumably reflecting isolated diastolic heart failure (25,26).
We have previously shown that incident CHD among
individuals with glucose disorders is related to elevated
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Barzilay et al.
Fasting Glucose and CHF in Elderly Patients With DM
JACC Vol. 43, No. 12, 2004
June 16, 2004:2236–41
Table 4. Cox Regression Models of the Association of Fasting Blood Glucose Level per 1 SD
Increase of Fasting Glucose (60.6 mg/dl) and as Quartiles of Fasting Glucose Levels on Incident
CHF Among Diabetic Participants in the CHS With Baseline CHD With or Without Incident
MI or CHD Event
Fasting glucose increase
of 60.6 mg/dl
Fasting glucose quartiles
1st
2nd
3rd
4th
Model I
Model II*
Model III†
1.16 (0.95, 1.41)
1.31 (1.06, 1.61)
1.27 (1.24, 1.58)
1.00
0.64 (0.33, 1.25)
1.03 (0.56, 1.89)
1.39 (0.79, 2.44)
1.00
0.63 (0.31, 1.29)
1.17 (0.62, 2.19)
1.59 (0.89, 2.83)
1.00
0.56 (0.27, 1.14)
1.29 (0.68, 2.45)
1.60 (0.87, 2.94)
Continuous fasting glucose hazard ratios are in SD units of 60.6 mg/dl. Quartiles of fasting glucose (mg/dl): I ⫽ 61 to 132; II
⫽ 133 to 152; III ⫽ 153 to 190; IV ⫽ 191 to 657. *Adjusted for age, systolic blood pressure, C reactive protein level, uric acid
level, smoking status (never, former, present), body mass index, waist circumference, and oral hypoglycemic index and insulin
use (as compared with no treatment for diabetes mellitus, i.e., newly diagnosed diabetes mellitus). All are statistically significant
predictors of congestive heart failure (CHF), except insulin use; †Adjusted for factors in model II plus incident myocardial
infarction (MI) and coronary heart disease (CHD) event before CHF. All are significant predictors of CHF other than insulin
use.
CHS ⫽ Cardiovascular Health Study.
fasting glucose levels (27). In that analysis, 20 mg/dl
increments of fasting glucose levels increased CHD risk by
6% (95% confidence interval 1.00 to 1.12). Thus, it is not
surprising that in those in whom CHF occurred in association with prevalent CHD that the risk of CHF was
associated with the fasting glucose level.
Several other points regarding our results should be
noted. First, of the total CHF events in this diabetic cohort,
only 33% (68 of 206) occurred in the absence of clinical
CHD. This value is lower than that found in the Framingham Heart study (28). This difference, in all likelihood,
reflects the higher rate of CHD in people with DM.
Second, among those in whom echocardiographic reports
were available at the time of CHF diagnosis, ⬃45% to 60%
had normal or borderline systolic ventricular function (depending on prevalent or incident MI or CHD events). This
is in keeping with recent population-based data (29). Third,
approximately one-half of the cohort had untreated DM.
Most were newly diagnosed diabetic individuals. This is
similar to prior studies of DM in which one-half of
individuals with DM are unaware of having it (30).
The strength of this study is its methodology. It allowed
for the evaluation of baseline risk factors as well as incident
events. It was population-based and included women and
minorities. Disadvantages of this study should also be noted.
First, institutionalized individuals and those with short life
expectancy were excluded. Thus, the sample is primarily of
the relatively healthy elderly, and results cannot be extrapolated to those who were very ill. On the other hand, the
relatively long follow-up of CHS should diminish this
effect. Second, a fasting glucose level was used and not a
measure of overall glucose control, such as glycosylated
hemoglobin. Many epidemiological studies rely on fasting
glucose levels. There was, however, a strong correlation
between the baseline fasting glucose level and the hemoglobin A1c level in a subset of the study cohort done one year
after baseline testing. This suggests that the fasting glucose
level was related to overall glucose control. It also suggests
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that elevated glucose levels tracked over time and reflected
continued elevated levels. Third, angiographic data are not
available in CHS. The degree of underlying CHD in those
without clinical CHD, therefore, cannot be assessed.
In conclusion, elevated fasting glucose levels in older
adults with DM are associated with the risk of CHF in both
those with and without MI/CHD. Ongoing prospective
diabetes studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, will be able to
determine if better glucose control results in a reduction of
CHF risk.
Reprint requests and correspondence: Dr. Joshua I. Barzilay,
Kaiser Permanente of Georgia, 200 Crescent Center Parkway,
Tucker, Georgia 30084. E-mail: [email protected].
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