Fasting Glucose Is an Important Independent Risk Factor
for 30-Day Mortality in Patients With Acute
Myocardial Infarction
A Prospective Study
Mahmoud Suleiman, MD; Haim Hammerman, MD; Monther Boulos, MD;
Michael R. Kapeliovich, MD, PhD; Abeer Suleiman, BSc; Yoram Agmon, MD;
Walter Markiewicz, MD; Doron Aronson, MD
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Background—Stress hyperglycemia in patients with acute myocardial infarction has been associated with increased
mortality. Most studies looked at the relationship between admission glucose (AG) and outcome; limited information
is available about the clinical significance of fasting glucose (FG).
Methods and Results—We prospectively studied the relationship between FG and 30-day mortality in 735 nondiabetic
patients with acute myocardial infarction. FG (ⱖ8-hour fast within 24 hours of admission) and AG were measured in
each patient. At 30 days, 9 deaths (2%) occurred in patients with normal FG, and 11 (10%), 14 (13%), and 31 (29%)
deaths occurred in the first, second, and third tertiles of elevated FG, respectively. Compared with normal FG (⬍110
mg/dL), the adjusted OR for 30-day mortality progressively increased with higher tertiles of elevated FG (first tertile,
4.6; 95% CI, 1.7 to 12.7; P⫽0.003; second tertile, 6.4; 95% CI, 2.5 to 16.6; P⬍0.0001; third tertile, 11.5; 95% CI, 4.7
to 20.0; P⬍0.0001). Compared with patients categorized as having normal AG (⬍140 mg/d), the adjusted ORs for
tertiles of elevated AG were as follows: first tertile, 1.4 (95% CI, 0.5 to 3.8; P⫽0.54); second tertile, 3.0 (95% CI, 1.3
to 7.0; P⫽0.01); and third tertile, 4.4 (95% CI, 2.0 to 9.7; P⬍0.0001). Compared with patients with normal FG and AG,
the adjusted ORs for 30-day mortality were 0.71 (95% CI, 0.15 to 3.4; P⫽0.67) in patients with elevated AG and normal
FG, 3.4 (95% CI, 1.1 to 10.4; P⫽0.03) for patients with normal AG glucose and elevated FG, and 9.6 (95% CI, 3.5 to
26.0; P⬍0.0001) for patients with both elevated FG and AG. Comparing nested models showed that including AG failed
to improve the prediction of the model based on FG (␹2⫽5.4, 3 df, P⫽0.15). In contrast, the addition of FG classes to
the model based on AG improved model prediction (␹2⫽22.4, 3 df, P⬍0.0001).
Conclusions—There is a graded relation between elevated FG and AG and 30-day mortality in patients with acute
myocardial infarction. FG is superior to AG in the assessment of short-term risk. (Circulation. 2005;111:754-760.)
Key Words: glucose 䡲 myocardial infarction 䡲 prognosis 䡲 stress
T
he finding of abnormally elevated blood glucose, common among patients with acute myocardial infarction,1–3
is often referred to as stress hyperglycemia. Several studies
have shown that raised blood glucose concentrations on
admission are associated with increased mortality and congestive heart failure.4 – 8
Most previous reports studied the relationship between admission
glucose (AG) level and outcome1,6–10; limited information is available about the clinical significance of fasting glucose (FG) in acute
myocardial infarction.5,11,12 Furthermore, the relative risk associated
with fasting hyperglycemia was not adjusted for other important
factors that affect outcome. In addition, the ability of fasting
hyperglycemia to predict mortality was evaluated with dichotomous
groupings, eg, those above and below an arbitrary cut point, rather
than through a study of its predictive value over the entire range of
its possible values. Finally, the relative prognostic information
provided by FG and AG in patients with acute myocardial infarction
has not been evaluated.
In the present study, we prospectively evaluated the predictive value of stress hyperglycemia for 30-day mortality in
nondiabetic patients with acute myocardial infarction. The
prognostic importance of both FG and AG was considered
and compared.
Methods
Patients
The study included all patients presenting to the intensive coronary
care unit of Rambam Medical Center with acute myocardial infarc-
Received July 9, 2004; revision received October 21, 2004; accepted October 28, 2004.
From the Department of Cardiology, Rambam Medical Center, and the Bruce Rappaport Faculty of Medicine, Haifa, Israel.
Correspondence to Doron Aronson, MD, Department of Cardiology, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel. E-mail
[email protected]
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000155235.48601.2A
754
Suleiman et al
tion between July 2001 and January 2004. The investigational review
committee on human research approved the study protocol, and
patients gave informed consent.
Myocardial infarction was diagnosed on the basis of the European
Society of Cardiology and American College of Cardiology criteria.13 Exclusion criteria were admission at ⬎24 hours from symptom
onset, known inflammatory disease, and surgery or trauma within the
previous month. Qualifying patients received thrombolytic therapy
(tissue plasminogen activator or streptokinase) or underwent primary
coronary angioplasty according to the discretion of the attending
cardiologist.
Plasma Glucose Measurements
The first blood sample for plasma glucose measurement was taken in all
patients on admission. A second sample was obtained after an overnight
fast of ⱖ8 hours within 24 hours of admission. Intravenous glucose
solutions were not allowed, but adrenergic agents were used if clinically
indicated. Plasma glucose was enzymatically determined with the
glucose oxidase method using an AutoAnalyzer (Hitachi Inc).
Study End Points and Definitions
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Patients who had a clinical diagnosis of diabetes before enrollment in
the study were classified as having known diabetes. Patients were
classified as having diabetes on the basis of history, regardless of
duration of disease, or need for antidiabetic agents. The diagnosis
was established if the patient had been informed of the diagnosis by
a physician before the admission or was taking oral antihyperglycemic agents, taking insulin, or receiving diet therapy. Glycohemoglobin on admission was not used because it is not recommended for the
diagnosis of diabetes by recent guidelines.14,15
Classification of normal FG and AG levels in patients who had not
been diagnosed with diabetes was made prospectively according to
the criteria of the American Diabetes Association14 and the 1999
report of the World Health Organization.16 On the basis of fasting
plasma glucose, patients were classified as having normal FG using
a cutoff level of ⬍110 mg/dL (6.1 mmol/L).14,16 Patients with
elevated FG levels (FG ⱖ110 mg/dL) were divided into tertiles of
elevated FG. While the study was in progress, the American Diabetes
Association lowered the threshold for normal glucose to ⬍100
mg/dL (5.6 mmol/L).15 Therefore, additional analyses were made
with this new threshold.
On the basis of admission (random) plasma glucose, patients were
classified as having normal levels using a cutoff level of ⬍140
mg/dL (7.8 mmol/L).14,16 Patients with elevated AG levels (FG
ⱖ140 mg/dL) were divided into tertiles of elevated AG.
The primary end point of the study was all-cause mortality within 30
days. Secondary end points included the combined end point of death
and heart failure developing ⬎24 hours after admission. Development
of heart failure was defined as rales over more than half of the lung field
and evidence of pulmonary congestion on a chest radiograph. Patients
were followed up throughout their hospital stay. After hospital discharge, clinical end-point information was acquired by reviewing the
national death registry and by contacting each patient individually and
independently reviewing the hospital records for major clinical events if
the patient had been rehospitalized.
Statistical Analysis
Continuous variables are presented as either means (⫾SD) or
medians (with interquartile ranges); categorical variables, as numbers and percentages. The baseline characteristics of group categorized by FG level were compared by use of ANOVA for continuous
variables and by the ␹2 statistic for noncontinuous variables. Correlations among continuous variables were assessed with Spearman’s
rank correlation coefficient.
FG and AG were modeled with indicator variables divided into
normal (⬍110 mg/dL for FG, ⬍140 mg/dL for AG)14 and tertiles of
elevated FG and AG. The ORs and 95% CIs compared with normal
levels were calculated for patients in the first, second, and third
tertiles of elevated FG and AG.
Fasting Glucose in Myocardial Infarction
755
Event-free survival curves were estimated by the Kaplan-Meier
method and compared with the log-rank test. Univariate and multivariate logistic regression models were used to calculate ORs and
95% CIs for various glucose categories after adjustment for the
following baseline clinical characteristics: age, gender, previous
infarction, heart rate and systolic blood pressure on admission, Killip
class on admission, history of hypertension, presence of ST-elevation
infarction, presence of anterior infarction, peak creatine kinase, and
reperfusion therapy with either thrombolytic agents or primary
angioplasty. Variables found to show marginal association with
30-day mortality in the univariate analysis (P⬍0.20) were used in the
multivariate model.
Nested models were compared by use of ␹2 likelihood ratio tests
to determine whether logistic regression models that included categories of FG and AG provided a significantly better fit than did
logistic regression models limited to FG and vice versa. In addition,
comparison of nonnested models including either FG or AG was
performed by calculating Akaike’s information criterion, followed
by Akaike weights, which is an estimate of the probability that a
given model is the best model of those studied.17,18
Receiver-operating characteristics analysis was used to assess the
ability of various levels of FG and AG to predict 30-day mortality.
The receiver-operating characteristics curve indicates the probability
of a true-positive result as a function of the probability of a
false-positive result for all possible threshold values.19 Differences
were considered statistically significant at the 2-sided P⬍0.05 level.
Statistical analyses were performed with SPSS statistical software,
version 11.5.
Results
Subject Sample and Demographics
Between July 2001 and January 2004, a total of 735 nondiabetic patients who presented with acute myocardial infarction were enrolled. Data were also collected from 310 patients
with known diabetes who were admitted during the study
period. The median FG and AG levels of patients without
prior diagnosis of diabetes were 115 mg/dL (interquartile
range, 97 to 149 mg/dL) and 147 mg/dL (interquartile range,
117 to 218 mg/dL), respectively. The median length of time
between AG and FG measurements was 14.7 hours.
The clinical characteristics of nondiabetic patients according to categories of FG (normal FG, tertiles of elevated FG,
and diabetes) are shown in Table 1. Elevated levels of FG
were associated with older age, male gender, and history of
hypertension. Patients presenting with elevated FG were
more likely to have ST-segment elevation or anterior infarction and had higher heart rates and Killip class on admission.
Use of aspirin, ␤-blockers, ACE inhibitors, and statins was
less frequent in patients with elevated FG. They were more
likely to be treated with primary angioplasty.
Relation of Stress Hyperglycemia to 30-Day Mortality
A total of 65 deaths (8.8%) occurred at 30 days. KaplanMeier survival curves (Figure 1) and unadjusted logistic
regression analysis showed a striking increase in the risk of
30-day mortality with increasing tertiles of elevated FG
(Table 2). After adjustment for other important covariates,
elevated FG remained a strong independent predictor of
30-day mortality (Table 2).
Using the new American Diabetes Association criteria for
normal FG (⬍100 mg/dL)15 resulted in 129 patients (17.6%)
initially classified as having normal FG being reclassified as
having elevated FG. With this cutoff value for normal FG, the
adjusted ORs for 30-day mortality in tertiles of elevated FG
756
Circulation
TABLE 1.
February 15, 2005
Baseline Clinical Characteristics of the Study Groups
Tertiles of Elevated FG, mg/dL*
Normal FG
(n⫽409)
First, 100 –121
(n⫽109)
Second, 122–138
(n⫽109)
Third, ⱖ139
(n⫽108)
Age, y
59⫾13
61⫾12
62⫾14
Men, n (%)
347 (85)
88 (81)
81 (74)
81 (20)
22 (20)
Characteristic
Previous infarct, n (%)
Diabetes
(n⫽310)
P for Trend
64⫾13
65⫾11
⬍0.0001
84 (78)
213 (69)
⬍0.0001
17 (16)
28 (26)
94 (30)
0.001
Smoking, n (%)
275 (67)
63 (58)
69 (63)
63 (58)
93 (30)
⬍0.0001
History of hypertension, n (%)
180 (44)
56 (51)
55 (51)
62 (57)
208 (67)
⬍0.0001
Systolic BP at admission, mm Hg
128⫾23
132⫾31
128⫾30
127⫾32
133⫾32
0.36
Heart rate at admission, bpm
74⫾17
79⫾17
78⫾17
85⫾25
84⫾19
⬍0.0001
Killip class at admission
1.2⫾0.5
1.5⫾0.9
1.4⫾0.9
2.0⫾1.2
1.7⫾1.0
⬍0.0001
ST-elevation infarction, n (%)
285 (70)
82 (75)
90 (83)
87 (81)
202 (65)
0.45
Anterior infarction, n (%)
170 (42)
51 (47)
49 (45)
60 (56)
143 (46)
934 (470–1945)
1311 (802–2684)
1715 (769–2797)
2353 (1005–4672)
1869 (773–3202)
Peak CK, IU/L
0.1
⬍0.0001
Initial medical therapies, n (%)
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Aspirin
403 (99)
106 (96)
105 (98)
99 (92)
292 (94)
0.001
␤-Blockers
362 (89)
100 (90)
83 (78)
87 (81)
266 (86)
0.09
ACE inhibitors/A-II receptor blockers
331 (81)
87 (80)
86 (79)
76 (70)
270 (87)
0.15
Statins
260 (64)
59 (54)
62 (57)
52 (49)
188 (61)
0.28
Reperfusion therapy, n (%)
Thrombolysis
115 (28)
31 (28)
24 (22)
26 (24)
54 (17)
0.001
Primary angioplasty
87 (21)
26 (24)
34 (31)
34 (32)
55 (18)
0.63
BP indicates blood pressure; CK, creatine kinase; and Ang II, angiotensin II. Values are expressed as mean⫾SD or median (interquartile range) as appropriate.
Trends for categorical variables were calculated with the Cochran-Armitage trend test.
*To convert from mg/dL to mmol/L, multiply plasma glucose values by 0.0555.
compared with normal FG were as follows: first tertile, 2.3
(95% CI, 0.63 to 8.7; P⫽0.021); second tertile, 7.3 (95% CI,
2.3 to 22.8; P⫽0.0006); and third tertile, 11.7 (95% CI, 4.0 to
34.7; P⬍0.0001).
Similar relationships existed when patients were classified
according to AG levels. The adjusted OR for excess 30-day
mortality progressively increased with higher tertiles of
elevated AG compared with normal FG (Table 3).
Because the selection of a “normal” value for FG and AG in
the setting of acute myocardial infarction is likely to be somewhat arbitrary,14,15 receiver-operating characteristics curves of
the ability of various glucose levels to predict 30-day mortality
were plotted. The threshold levels of FG and AG that maximized
the combined sensitivity and specificity for the prediction of
30-day mortality were close to the cutoff levels that were
prospectively chosen (114 mg/dL for FG, 151 mg/dL for AG).
Figure 1. Kaplan-Meier cumulative survival curves of patients with normal FG
and tertiles of elevated FG (comparison
by log-rank test).
Suleiman et al
TABLE 2.
Fasting Glucose in Myocardial Infarction
757
Unadjusted and Adjusted Logistic Regression for 30-Day Mortality According to Categories of FG Levels*
FG, mg/dL†
n
Events,
n (%)
Unadjusted
OR (95% CI)
P for
Trend
P
Adjusted
OR (95% CI)
P for
Trend
P
Death
⬍0.0001
⬍0.0001
Normal (⬍110)
409
9 (2.2)
1.0
Elevated, first tertile (110–121)
109
11 (10.0)
5.0 (2.0–12.4)
0.001
4.6 (1.7–12.7)
1.0
0.003
Elevated, second tertile (122–138)
109
14 (12.8)
6.6 (2.8–15.6)
⬍0.0001
6.4 (2.5–16.6)
⬍0.0001
Elevated, third tertile (ⱖ139)
108
31 (28.7)
17.9 (8.2–39.1)
⬍0.0001
11.5 (4.7–20.0)
⬍0.0001
Normal (⬍110)
409
23 (5.6)
1.0
Elevated, first tertile (110–121)
109
17 (15.6)
3.1 (1.6–6.0)
0.0009
2.8 (1.4–5.9)
Elevated, second tertile (122–138)
109
21 (19.3)
4.0 (2.1–7.6)
⬍0.0001
3.9 (1.9–7.8)
Elevated, third tertile (ⱖ139)
108
37 (31.5)
8.7 (4.9–15.6)
⬍0.0001
5.6 (2.8–10.9)
Death and heart failure
⬍0.0001
⬍0.0001
1.0
0.006
0.0002
⬍0.0001
*The final model was adjusted for age, gender, history of hypertension, presence of anterior infarction and ST-elevation infarction, Killip class, heart rate and blood
pressure on admission, and use of reperfusion therapy.
†To convert from mg/dL to mmol/L, multiply plasma glucose values by 0.0555.
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Comparison of FG and AG in Predicting
30-Day Mortality
There was a moderate correlation between FG and AG
(Spearman’s ␳, 0.40; P⬍0.0001). We found only a modest
relationship between the FG and AG sets of criteria for stress
hyperglycemia. Among 735 patients with no history of
diabetes, 294 patients (40%) were classified as having both
normal FG and AG, 142 (19%) as having elevated FG and
normal AG, 115 (16%) as having elevated AG and normal
FG, and 184 (25%) as having both elevated FG and AG.
Compared with patients with normal FG and AG, the
adjusted ORs for 30-day mortality were 0.71 in patients with
elevated AG and normal FG (95% CI, 0.15 to 3.4; P⫽0.67),
3.4 for patients with normal AG and elevated FG (95% CI,
1.1 to 10.4; P⫽0.03), and 9.6 for patients with both elevated
FG and AG (95% CI, 3.5 to 26.0; P⬍0.0001) (Figure 2).
Log-likelihood ratio tests were used to compare the fit of
predictive models that were based on categories of FG (Table
2) combined with categories of AG (Table 3) and vice versa.
Comparing nested models showed that including the AG
classes did not significantly improve the prediction of the
model based on FG and other risk factors for 30-day mortality
TABLE 3.
(␹2⫽5.4, 3 df, P⫽0.15) or for 30-day mortality and heart
failure (␹2⫽4.6, 3 df, P⫽0.20). In contrast, the addition of FG
classes to the model based on AG and other risk factors
significantly improved the prediction of the model for both
30-day mortality (␹2⫽22.4, 3 df, P⬍0.0001) and 30-day
mortality and heart failure (␹2⫽22.3, 3 df, P⫽0.0001).
Overall, AG concentrations were not independently related to
mortality after adjustment for FG concentrations. Similar
results were obtained when nonnested models were compared. The model containing FG classes yielded the best
Akaike’s information criterion and demonstrated a 99%
probability of representing the best model.
Effect of Diabetes
Of the 310 patients with known diabetes, 42 were receiving
insulin treatment with or without oral agents (14%), 184 were
receiving oral agents (59%), and 84 were on diet therapy
(27%). The median FG and AG levels of patients with known
diabetes were significantly higher than those of patients
without diabetes (FG: Mann-Whitney P⬍0.0001; difference
in medians, 54 mg/dL; and AG: Mann-Whitney P⬍0.0001;
difference in medians, 111 mg/dL). There was a significant
Unadjusted and Adjusted Logistic Regression for 30-Day Mortality According to Categories of AG Levels*
AG, mg/dL†
Unadjusted
OR (95% CI)
P
P for
Trend
Adjusted
OR (95% CI)
n
Events (%)
P
Normal (⬍140)
436
18 (4.1)
1.0
Elevated, first tertile (140–156)
100
6 (6.0)
1.5 (0.6–3.8)
0.42
1.4 (0.5–3.8)
0.54
Elevated, second tertile (157–183)
100
14 (14.0)
3.8 (1.8–7.9)
⬍0.0001
3.0 (1.3–7.0)
0.01
99
27 (27.3)
8.7 (4.6–16.6)
⬍0.0001
4.4 (2.0–9.7)
⬍0.0001
Normal (⬍140)
409
36 (8.8)
1.0
Elevated, first tertile (140–156)
109
10 (9.2)
12.2 (0.6–2.6)
P for
Trend
Death
Elevated, third tertile (ⱖ184)
⬍0.0001
1.0
0.001
Death and heart failure
⬍0.0001
0.58
1.0
1.1 (0.5–2.4)
0.0002
0.87
Elevated, second tertile (157–183)
109
21 (19.2)
3.0 (1.6–5.3)
0.0003
2.7 (1.4–5.2)
0.004
Elevated, third tertile (ⱖ184)
108
31 (28.7)
5.1 (2.9–8.7)
⬍0.0001
3.0 (1.6–5.7)
0.001
*Adjusted for the covariates listed in Table 2.
†To convert from mg/dL to mmol/L, multiply plasma glucose values by 0.0555.
758
Circulation
February 15, 2005
Figure 2. Kaplan-Meier cumulative survival curves according to presence or
absence of elevated FG and AG levels
(comparison by log-rank test).
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interaction between diabetes and both FG (P⫽0.007) and
AG (P⫽0.02) because the relationship between increasing
levels of AG or FG and 30-day mortality was much weaker
among patients with diabetes.
To evaluate whether previously undiagnosed diabetes
could account in part for the relationship between FG and
outcome in nondiabetic patients, we performed a multivariate
logistic regression analysis using the combined data from
patients with and without previously diagnosed diabetes. In
this model, patients were divided into 4 groups. Patients
without a previous diagnosis of diabetes were classified
according to the American Diabetes Association14 as having
normal FG, impaired FG, or FG in the diabetes range (a
category that by definition includes all patients with undiagnosed diabetes); the fourth group included patients with
known diabetes. Compared with patients with normal FG, the
adjusted OR for 30-day mortality was much higher in patients
without previous diagnosis of diabetes and FG in the diabetes
range (ⱖ126 mg/dL [7.0 mmol/L]) compared with patients
with known diabetes (Table 4).
Discussion
In the present study, we prospectively evaluated the prognostic value of fasting hyperglycemia in nondiabetic patients
presenting with acute myocardial infarction. Compared with
patients who maintain normal FG levels, those who develop
elevated FG have more adverse baseline clinical characteristics. However, fasting hyperglycemia remains a strong and
independent predictor of 30-day mortality after adjustment
for established clinical predictors of adverse outcome among
patients with acute myocardial infarction,20,21 with a striking
increase in short-term mortality with small increases of FG
above normal levels. Furthermore, FG concentrations are
better predictors of mortality than AG.
TABLE 4. Unadjusted and Adjusted Logistic Regression for 30-Day Mortality According to the Level of FG
and Presence of Known Diabetes*
End Point
n
Events (%)
Unadjusted
OR (95% CI)
P
Adjusted
OR (95% CI)
P
Death
Normal FG (⬍110 mg/dL)†
409
9 (2.2)
1.0
Impaired FG (110–125 mg/dL)
145
14 (9.7)
4.8 (2.0–11.2)
0.0004
4.0 (1.5–10.5)
1.0
0.004
FG in the diabetes range (ⱖ126 mg/dL)
181
42 (23.2)
13.4 (6.4–28.3)
⬍0.0001
10.2 (4.4–23.7)
⬍0.0001
Previously known diabetes
310
35 (11.3)
5.7 (2.7–11.0)
⬍0.0001
2.4 (1.03–5.5)
0.04
Normal FG (⬍110 mg/dL)
409
24 (5.9)
1.0
Impaired FG (110–125 mg/dL)
145
22 (15.2)
3.0 (1.6–5.6)
FG in the diabetes range (ⱖ126 mg/dL)
181
56 (30.9)
6.9 (4.1–11.8)
Previously known diabetes
310
48 (15.5)
3.1 (1.8–5.2)
Death and heart failure
*Adjusted for the covariates listed in Table 2.
†To convert from mg/dL to mmol/L, multiply plasma glucose values by 0.0555.
1.0
0.0005
2.6 (1.3–5.0)
0.004
⬍0.0001
5.8 (3.3–10.3)
⬍0.0001
⬍0.0001
1.6 (0.9–2.9)
0.08
Suleiman et al
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In an overview of previous reports using data from 1856
patients, Capes et al4 calculated a pooled unadjusted relative
risk of 3.9 (95% CI, 2.9 to 5.4) for in-hospital mortality in
patients without diabetes who had stress hyperglycemia,
defined heterogeneously as elevated FG or AG. These authors
noted varying definitions of stress hyperglycemia among
studies, ranging from 119 mg/dL (6.6 mmol/L) to 200 mg/dL
(11.1 mmol/L) for random glucose and from 110 mg/L
(6.1 mmol/L) to 140 mg/dL (7.8 mmol/L) for FG.4 This
resulted in a marked difference in the proportion of nondiabetic patients defined as having stress hyperglycemia (3% to
71%).
There is a paucity of data on the potential use of FG for risk
stratification in patients with acute myocardial infarction,5,11,12 because most studies used glucose concentration on
admission.1,4,6 –10 Ravid et al12 and Soler et al11 reported a
higher unadjusted prevalence of in-hospital mortality among
nondiabetic patients with elevated FG. Using a cutoff value of
144 mg/dL (8 mmol/L) for fasting hyperglycemia, O’Sullivan
et al5 reported a relative risk of 2.8 (95% CI, 0.9 to 8.3) for
in-hospital mortality after adjustment for age. Recently,
Zeller et al22 studied the prognostic value of impaired FG
(110 to 126 mg/dL) determined at days 4 and 5 after
admission. Impaired FG was an independent predictive factor
for cardiogenic shock (adjusted OR, 2.8; 95% CI, 1.08 to
7.49; P⫽0.005) but failed to be an independent predictor of
in-hospital death.
Our study confirms the observations of smaller studies and
extends them in several important ways. First, stress hyperglycemia remains a strong and independent predictor of
30-day mortality after adjustment for established clinical
predictors of adverse outcome among patients with acute
myocardial infarction.20,21 Second, in the present study, we
avoided the use of a dichotomous definition of stress hyperglycemia. Our results indicate that the risk for 30-day
mortality among nondiabetic subjects with FG within the
normal range is very low. Within the range of elevated FG
levels, the risk increases dramatically across tertiles of elevated FG. A substantial increased risk for short-term mortality was observed at any level of abnormal FG and well below
the diabetic threshold. Third, although elevations of both FG
and AG concentrations were significant independent predictors of mortality when used alone, our results indicate that
elevated FG concentrations are better predictors of mortality
than AG. In patients with normal FG, elevated AG did not
incur an increased risk of death compared with patients with
normal FG and AG concentrations. In contrast, patients with
elevated FG and normal AG had a 3-fold increase in
mortality. Furthermore, when categories (tertiles) of elevated
FG are used for risk stratification, elevated AG did not
contribute significantly to the prediction of mortality,
whereas adding FG categories to models containing AG
provided additional prognostic information. The superiority
of FG over random glucose levels in predicting outcome
probably results from factors such as differences in the
amount of caloric intake and time since the last meal.
Several hypotheses (which are not mutually exclusive)
have been put forward to explain the relation between stress
hyperglycemia and poor outcome. Stress hyperglycemia may
Fasting Glucose in Myocardial Infarction
759
be a marker of extensive myocardial damage, reflecting a
surge of stress hormones such as catecholamines and cortisol
that produce or augment an insulin-resistant state.1,23 Relative
insulin deficiency and excess catecholamines reduce glucose
uptake by the ischemic myocardium and promote lipolysis
and increased circulating free fatty acids. The latter inhibit
glucose oxidation (the “glucose–fatty acid cycle”) and are
toxic to ischemic myocardium, resulting in increased membrane damage, arrhythmias, and reduced contractility.24 –27
Alternatively, elevated blood glucose levels per se adversely affect outcome through the cumulative effects of
several mechanisms, including induction of endothelial dysfunction,28 oxidative stress,28,29 hypercoagulability, and impaired fibrinolysis.30 However, the marked increase in risk for
30-day mortality with only mild elevations of FG argues
against a toxic effect of elevated blood glucose, unless
acceleration of these cellular alterations is exquisitely sensitive to small differences in plasma glucose levels. The finding
that FG has a stronger association with mortality than known
diabetes is also inconsistent with important detrimental effects of hyperglycemia.
Study Limitations
The prevalence of undiagnosed diabetes varies from 4% to
30% among patients admitted to the coronary care unit.2,3
Diabetes can be differentiated from stress hyperglycemia
with certainty only after the acute phase of the infarction.
Thus, any attempt to identify undiagnosed diabetes in our
study would have been biased because patients must survive
the acute phase to be diagnosed. It has been suggested that
HbA1c be used to distinguish between stress hyperglycemia
and hyperglycemia resulting from undiagnosed diabetes.31
However, there is a significant overlap in HbA1c levels
between patients with acute myocardial infarction and known
diabetes, newly diagnosed diabetes, and no diabetes.3 In
addition, HbA1c is not recommended for the diagnosis of
diabetes by recent guidelines even in stable subjects.15
It has been suggested that undiagnosed diabetes may
explain part of the mortality and morbidity associated with
stress hyperglycemia.4,10,31 We addressed this possibility by
comparing the outcome of patients with known diabetes and
patients with no previous history of diabetes who presented
with FG in the diabetic range in the entire study sample. By
definition, all patients with undiagnosed diabetes are untreated and should have an FG level ⱖ126 mg/dL.14 However, the risk associated with prior diagnosis of diabetes was
considerably lower compared with that of having FG in the
diabetes range in the absence of prior diagnosis of diabetes. In
this context, it is important to emphasize that a large number
of studies in patients with acute myocardial infarction have
shown that diabetes increases the risk of short-term mortality
1.5- to 2-fold.30 Thus, the presence of undiagnosed diabetes,
if anything, would lead to an underestimation of true risk
associated with stress hyperglycemia.
Conclusions
In nondiabetic patients with acute myocardial infarction,
there is a graded relation between elevated FG and AG and
30-day mortality. FG is superior to random glucose measurement on admission with regard to the assessment of short-
760
Circulation
February 15, 2005
term risk. FG concentrations may serve as a simple marker to
help clinicians stratify risk for optimal triage and
management.
References
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
1. Oswald GA, Smith CC, Betteridge DJ, Yudkin JS. Determinants and
importance of stress hyperglycaemia in non-diabetic patients with myocardial infarction. BMJ (Clin Res Ed). 1986;293:917–922.
2. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L,
Malmberg K. Glucose metabolism in patients with acute myocardial
infarction and no previous diagnosis of diabetes mellitus: a prospective
study. Lancet. 2002;359:2140 –2144.
3. Tenerz A, Lonnberg I, Berne C, Nilsson G, Leppert J. Myocardial
infarction and prevalence of diabetes mellitus: is increased casual blood
glucose at admission a reliable criterion for the diagnosis of diabetes? Eur
Heart J. 2001;22:1102–1110.
4. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and
increased risk of death after myocardial infarction in patients with and
without diabetes: a systematic overview. Lancet. 2000;355:773–778.
5. O’Sullivan JJ, Conroy RM, Robinson K, Hickey N, Mulcahy R.
In-hospital prognosis of patients with fasting hyperglycemia after first
myocardial infarction. Diabetes Care. 1991;14:758 –760.
6. Leor J, Goldbourt U, Reicher-Reiss H, Kaplinsky E, Behar S. Cardiogenic
shock complicating acute myocardial infarction in patients without heart
failure on admission: incidence, risk factors, and outcome: SPRINT Study
Group. Am J Med. 1993;94:265–273.
7. Bellodi G, Manicardi V, Malavasi V, Veneri L, Bernini G, Bossini P,
Distefano S, Magnanini G, Muratori L, Rossi G, et al. Hyperglycemia and
prognosis of acute myocardial infarction in patients without diabetes
mellitus. Am J Cardiol. 1989;64:885– 888.
8. Yudkin JS, Oswald GA. Hyperglycaemia, diabetes and myocardial
infarction. Diabet Med. 1987;4:13–18.
9. Foo K, Cooper J, Deaner A, Knight C, Suliman A, Ranjadayalan K,
Timmis AD. A single serum glucose measurement predicts adverse
outcomes across the whole range of acute coronary syndromes. Heart.
2003;89:512–516.
10. Bolk J, van der Ploeg T, Cornel JH, Arnold AE, Sepers J, Umans VA.
Impaired glucose metabolism predicts mortality after a myocardial
infarction. Int J Cardiol. 2001;79:207–214.
11. Soler NG, Frank S. Value of glycosylated hemoglobin measurements
after acute myocardial infarction. JAMA. 1981;246:1690 –1693.
12. Ravid M, Berkowicz M, Sohar E. Hyperglycemia during acute myocardial infarction: a six-year follow-up study. JAMA. 1975;233:807– 809.
13. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction
redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition
of Myocardial Infarction. J Am Coll Cardiol. 2000;36:959 –969.
14. Report of the Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197.
15. Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller
J, Knowler WC, Lebovitz H, Lernmark A, Nathan D, Palmer J, Rizza R,
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Saudek C, Shaw J, Steffes M, Stern M, Tuomilehto J, Zimmet P.
Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care.
2003;26:3160 –3167.
Definition, Diagnosis, and Classification of Diabetes Mellitus and Its
Complications, Part 1: Diagnosis and Classification of Diabetes Mellitus.
Geneva, Switzerland: World Health Organization; 1999.
Wagenmakers EJ, Farrell S. AIC model selection using Akaike weights.
Psychon Bull Rev. 2004;11:192–196.
Sakamoto Y, Ishiguro M, Kitagawa G. Akaike Information Criterion
Statistics. Tokyo, Japan: KTK Scientific Publishers; 1986.
Hanley JA, McNeil BJ. A method of comparing the areas under receiver
operating characteristic curves derived from the same cases. Radiology.
1983;148:839 – 843.
Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons
M, Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality
in the era of reperfusion for acute myocardial infarction: results from an
international trial of 41,021 patients: GUSTO-I Investigators. Circulation.
1995;91:1659 –1668.
Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de
Lemos JA, Giugliano RP, McCabe CH, Braunwald E. TIMI risk score for
ST-elevation myocardial infarction: a convenient, bedside, clinical score
for risk assessment at presentation: an Intravenous nPA for Treatment of
Infarcting Myocardium Early II Trial Substudy. Circulation. 2000;102:
2031–2037.
Zeller M, Cottin Y, Brindisi MC, Dentan G, Laurent Y, Janin-Manificat
L, L’Huillier I, Beer JC, Touzery C, Makki H, Verges B, Wolf JE.
Impaired fasting glucose and cardiogenic shock in patients with acute
myocardial infarction. Eur Heart J. 2004;25:308 –312.
Oswald GA, Smith CC, Delamothe AP, Betteridge DJ, Yudkin JS. Raised
concentrations of glucose and adrenaline and increased in vivo platelet
activation after myocardial infarction. Br Heart J. 1988;59:663– 671.
Oliver MF, Kurien VA. Serum-free-fatty-acids and arrhythmias after
acute myocardial infarction. Lancet. 1969;2:1077–1078.
Lopaschuk GD, Stanley WC. Glucose metabolism in the ischemic heart.
Circulation. 1997;95:313–315.
Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of
the heart in diabetes, part I: general concepts. Circulation. 2002;105:
1727–1733.
Depre C, Vanoverschelde JL, Taegtmeyer H. Glucose for the heart.
Circulation. 1999;99:578 –588.
Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: a
clinical perspective. Endocr Rev. 2001;22:36 –52.
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda
Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M.
Normalizing mitochondrial superoxide production blocks three pathways
of hyperglycaemic damage. Nature. 2000;404:787–790.
Aronson D, Rayfield EJ, Chesebro JH. Mechanisms determining course
and outcome of diabetic patients who have had acute myocardial
infarction. Ann Intern Med. 1997;126:296 –306.
Husband DJ, Alberti KG, Julian DG. “Stress” hyperglycaemia during
acute myocardial infarction: an indicator of pre-existing diabetes? Lancet.
1983;2:179 –181.
Fasting Glucose Is an Important Independent Risk Factor for 30-Day Mortality in Patients
With Acute Myocardial Infarction. A Prospective Study
Mahmoud Suleiman, Haim Hammerman, Monther Boulos, Michael R. Kapeliovich, Abeer
Suleiman, Yoram Agmon, Walter Markiewicz and Doron Aronson
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Circulation. published online February 7, 2005;
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