Diabetes and Metabolism

Admission and fasting plasma glucose for estimating

risk of death of diabetic and nondiabetic patients
with acute coronary syndrome: nonlinearity of
hazard ratios and time-dependent comparison
Belen Cid-Alvarez,a Francisco Gude,b Carmen Cadarso-Suarez,c Eva Gonzalez-Babarro,a
Maria Xose Rodriguez-Alvarez,c Jose Maria Garcia-Acuna,a and Jose Ramon Gonzalez-Juanatey,a
Santiago de Compostela, Spain

Background In patients with acute coronary syndrome (ACS), increased plasma glucose levels are associated with
worse outcome. Our aim is to ascertain the values of admission and fasting glucose for prediction of death among patients with
ACS; and to compare their predictive capacities.
Methods The relationships of mortality to plasma glucose levels among 811 consecutive patients hospitalized with ACS
were estimated using spline Cox models. Blood samples were obtained upon admission and after overnight fast. The predictive
capacities of fasting and admission glucose were compared using time-dependent receiver operating characteristic curves.
Results

Fasting and admission glucose levels were higher among the 151 patients who died (18.6%) than among
survivors (P < .001). Among the 558 patients with no history of diabetes (68.8%) there was a J-shaped dependence of the alltime mortality hazard ratio on fasting glucose that persisted when adjusted for covariates: hazard was lowest at 110 mg/dL
(6.1 mmol/L), and significantly greater at levels <90 mg/dL (5.0 mmol/L) or >117 mg/dL (6.5 mmol/L). Likewise among nondiabetic patients, the predictive capacities of admission and fasting glucose were similar for forecast times of up to about
1 year, but for later times the area under the receiver operating characteristic curve was larger for fasting glucose than
admission glucose (P < .05). Neither admission nor fasting glucose levels discriminated among diabetic patients in regard to
risk of death.

Conclusions Both admission and fasting glucose may be used for triage of nondiabetic ACS patients; fasting
glucose may additionally be useful for long-term management, for which the relationship with the all-time mortality hazard
ratio is J-shaped. (Am Heart J 2009;158:989-97.)

Alterations of glucose metabolism are common among

patients admitted to hospital with acute coronary
syndrome (ACS), regardless of whether diabetes mellitus
has been diagnosed previously.1,2 ACS patients may
present with hyperglycemia during the acute period
(admission hyperglycemia) and/or exhibit hyper- or
hypoglycemic fasting plasma glucose levels during
hospitalization. These alterations have variously been

From the Departments of aCardiology and bClinical Epidemiology, Complejo Hospitalario

Universitario de Santiago, and cDepartment of Statistics and Operations Research,
University of Santiago, Instituto de Investigacion Sanitaria de Santiago, Santiago de
Compostela, Spain.
Submitted March 4, 2009; accepted October 9, 2009.
Reprint requests: Belen Cid-Alvarez, Cardiology Department, Hospital Clinico Universitario
de Santiago, Travesia da Choupana, s/n, 15706 Santiago de Compostela, Spain.
E-mail: belcid77@hotmail.com
0002-8703/$ - see front matter
2009, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2009.10.004

associated with larger infarct size,3 a greater incidence of

congestive heart failure,4 cardiogenic shock,5,6 and both
short- and long-term mortality.7-11
Admission hyperglycemia, which some studies have
found to be associated with less risk for patients with a
previous history of diabetes than for those without,9,12
has been reported to reflect or be associated with a stressinduced increase in insulin resistance and other stress
responses.13,14 Fasting glucose is more related to the
background metabolic state, depending not only on tissue
insulin sensitivity but also on the state of complex
hormonal and metabolic networks.15
Most previous comparisons of the prognostic values of
admission and fasting glucose have considered death and
survival rates at just one fixed time post-admission or by
the end of follow-up, without attempting to determine
how prognostic value may depend on forecast time.4,10,11
However, taking forecast time dependence into account
might be useful in clinical decision-making: in principle it

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990 Cid-Alvarez et al

is possible that while the acute event (admission

hyperglycemia) may strongly predict short-term risk, the
parameter more closely related to background metabolism (fasting glucose) may be a more sensitive predictor of
the maintenance of a high risk level over time.
In the present study we aimed to ascertain and
compare the abilities of admission and fasting glucose
to predict the death of ACS patients, distinguishing
between those with and those without a previous
diagnosis of diabetes mellitus. The nonlinear relationships
between glucose levels and risk of death were modeled
by means of cubic spline Cox analyses, and the predictive
values of admission and fasting glucose were characterized for forecast times of up to 4 years by means of timedependent receiver operating characteristics (ROCs), a
technique that as far as we know has not previously been
employed in this context.

Methods
Patients
The study group comprised the 811 patients admitted to our
coronary care unit between September 2003 and March 2007
with a tentative diagnosis of ACS that was confirmed in
accordance with the universal definition of myocardial infarction by the patient's presenting (i) a troponin I level >99th
percentile of our reference population (0.6 ng/mL) in at least 1
of 3 blood samples taken during the first 6 hours after
admission, (ii) electrocardiographic (ECG) changes indicative of
new ischemia (new ST-T changes, new left bundle branch block,
or the development of pathological Q waves), and/or iii)
imaging evidence of new loss of viable myocardium or new
regional wall motion abnormality.

Glucose measurements
Serum glucose was measured by the glucose oxidase method,
using a Siemens Advia 2400 AutoAnalyzer, in blood samples
taken upon admission and after an overnight fast of >8 hours
within 24 hours of admission. Patients were stratified into tertile
groups defined by fasting plasma glucose.

Ethics
All 811 patients agreed to participate in the study, which was
reviewed and approved by the regional ethics committee.

Outcome measures and definitions

Patients were classified as known diabetic patients if they had
been informed of this diagnosis by a physician before admission
or were on oral antihyperglycemic agents, insulin, or diet
therapy. Glycohemoglobin on admission was not used as a
criterion because it is not recommended for the diagnosis of
diabetes by recent guidelines.
The outcome studied was death from any cause before August
2007. Patients were followed up by the study team throughout
their hospital stay. After discharge, vital status information was
acquired by reviewing the Galician Health Registry, by contacting patients or their families individually and, if the patient had

been rehospitalized, by reviewing the hospital records of major

clinical events.

Statistical analysis
Single-variable Cox models were used to evaluate association
in the whole study group between the all-time risk of death (i.e.,
the risk of death at any time during the study) and each of the
baseline demographic and clinical variables, including admission and fasting glucose. For the latter, given the nonlinear
nature of the association, the models were constructed using
natural cubic splines, HR curves and their asymptotic 95% CIs
being defined relative to minimum risk values16; for the other
variables, linear models were used.17
Multivariable Cox models of all-time risk of death were also
constructed that, together with fasting glucose (which in the
single-variable analyses proved to have greater predictive value
than admission glucose), included variables of known
prognostic value, and variables of unproven prognostic value
that nevertheless emerged as significant predictors of mortality
in 2-covariate analyses with fasting glucose as the other
covariate. In view of the results obtained in the two-covariate
analysis with diabetes, independent multivariate Cox models
were constructed for diabetic and nondiabetic patients. In
both cases, the variables included because they proved
significant in the two-covariate analyses were age, heart
failure (Killip class 2), and ST-segment elevation myocardial
infarction (STEMI), as well as fasting glucose; in addition, the
inclusion of sex, previous coronary artery disease, hypertension, creatinine and anemia was forced. In all the analyses
described in this paragraph, splines were employed to model
glucose dependence.18
Taking data censoring into account, the log hazard ratios of
the unadjusted Cox models were used as criterion variables X to
construct time-dependent ROCs19 via the corresponding sensitivity and specificity functions: for given time t and criterion
threshold c,
sensitivity c; t = PXNcjTVt;
specificity c; t = PXVcjTNt;
where T is survival time. For each time t, the area under the
time-dependent ROC [AUC(t)] was calculated, and 95% CIs for
the AUC(t) curves and for the difference between the admission
and fasting glucose AUC(t) curves were constructed using a nonparametric small-sample bootstrap method in which the
underlying Cox models were recalculated for each resample.
All statistical analyses were carried out in R using the packages
survival (for fitting parametric Cox models), splines (for fitting
nonparametric Cox models), and survival ROC (for timedependent ROC curves). These packages are freely available at
http://cran.r-project.org.

Sources of funding and authorship

This work was supported by grants from the Carlos III Health
Institute, Spain (redINSCOR [RD06/0003/0016], redIAPP
[RD06/0018/0006]), and the Spanish Ministry of Science and
Technology (MTM2008-01603), Xunta de Galicia (INCITE08PXIB208113PR). F Gude was supported by a grant (BAE09/90052)
from the Instituto de Salud Carlos-III (Spanish Ministry of
Science and Technology). The authors are solely responsible for

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Cid-Alvarez et al 991

Table I. Baseline characteristics of patients according to vital status

No. of subjects (%)

Age (y)
Male sex, n (%)
Hypertension, n (%)
Known diabetes, n (%)
Dyslipaemia, n (%)
Smoking, n (%)
Prior CAD, n (%)
STEMI, n (%)
Killip class 2, n (%)
LVEF < 50%, n (%)
Atrial fibrillation, n (%)
Three-vessel disease, n (%)
Anemia, n (%)
Troponin I, ng/dL
Creatinine, mg/dL
Admission glucose,
mg/dL (mmol/L)
Fasting glucose,
mg/dL (mmol/L)

Non-survivors

Survivors

151 (19)
76 10
105 (69)
100 (66)
69 (46)
77 (51)
60 (40)
60 (40)
52 (34)
79 (52)
78 (52)
32 (21)
56 (57)
75 (50)
19 (3-45)
1.2 (1.0-1.6)
148 (111-217)

660 (81)
65 13
500 (76)
363 (55)
184 (28)
325 (49)
334 (51)
176 (27)
261 (39)
565 (86)
161 (24)
72 (11)
163 (30)
128 (19)
10 (2-40)
1.0 (0.8-1.1)
124 (106-175)

<.001
.138
.014
<.001
.916
.466
.003
.510
<.001
<.001
<.001
<.001
<.001
.061
<.001
<.001

135 (102-181)

114 (99-144)

<.001

CAD, Coronary artery disease. LVEF, left ventricular ejection fraction. Values are
means SDs, or medians with the corresponding interquartile range in parentheses,
as appropriate.
Coronary angiography results were available for 645 patients.

the design and conduct of this study, all study analyses, the
drafting and editing of the manuscript, and its final contents.

Results
Baseline and general
The 811 patients enrolled in the study were aged 67
13 years (mean SD), 206 (25%) were women, and 253
(31%) had a history of diabetes. The median duration of
follow-up was 18 months (range, 0-48 months), and 151
patients (18.6%) died. Nonsurvivors were older on
admission than survivors (76 10 vs 65 13 years, P <
.001), and were more likely to have a history of
hypertension (P = .014), diabetes (P < .001) and previous
myocardial infarction (P = .016), but there were no
significant differences between survivors and non-survivors as regards sex, smoking habit or dyslipemia. The
nonsurvivor group had higher incidences of three-vessel
disease and atrial fibrillation, smaller left ventricular
ejection fractions, higher serum creatinine levels at
admission, higher Killip classes, and were less likely to
receive coronary angiography and percutaneous intervention (P < .001 in all cases) (Table I).
Table II summarizes the characteristics of the patient
groups defined by fasting glucose tertiles. Among the
three patient groups defined by fasting glucose tertiles
there were significant differences in age (P < .001),
creatinine on admission (P = .052), peak troponin in
the first 6 hours (P < .001), and prevalences of heart
failure, diabetes and 3-vessel disease (P < .001 in all
three cases) (see Table II).

Table II. Baseline characteristics classified by fasting glucose tertiles

Fasting glucose,
mg/dL (mmol/L)

<106
(<5.8)

106-135
(5.8-7.5)

>135
(>7.5)

Age, y
65 14
68 13
70 11
Male sex, %
76
77
71
Hypertension, %
52
58
62
Diabetes, %
12
22
60
Dyslipaemia, %
49
44
55
Smoking, %
45
42
38
Prior CAD, %
32
25
30
STEMI, %
29
25
30
Killip class 2, %
15
18
29
Atrial fibrillation, %
9
16
16
Three-vessel disease, %
31
27
44
Anemia, %
25
24
26
Troponin I, ng/dL
5 (1-21)
15 (3-53)
17 (4-56)
Creatinine, mg/dL
1.09 0.60 1.11 0.57 1.21 0.70

P
<.001
.240
.080
<.001
.062
.358
.193
.193
<.001
.057
<.001
.954
<.001
.052

Values are means SDs, or medians with the corresponding interquartile range in
parentheses, as appropriate. CAD: coronary artery disease.
Coronary angiography results were available for 645 patients.

Glucose levels, mortality, and diabetes

Fasting and admission glucose levels were both higher
among non-survivors than survivors: 135 (102-181) versus
114 (99-144) mg/dL for fasting glucose (median [interquartile range]; 7.5 [5.6-10.0] versus 6.3 [5.5-8.0] mmol/
L), 148 (111-217) versus 124 (106-175) mg/dL (8.2 [6.112.0] versus 6.8 [5.8-9.7] mmol/L) for admission glucose.
For fasting glucose, the two-covariate analysis with
diabetes showed a statistically significant diabetes
glucose interaction (P = .02): among non-diabetic
patients, the single-variable analysis showed a clear Jshaped relationship between fasting glucose and log
hazard ratio, which was least for a fasting glucose level
of 106 mg/dL (5.9 mmol/L) (Figure 1, A), whereas
among known diabetic patients no level of fasting
glucose was associated with a significantly higher risk
of death (Figure 1, B). For admission glucose, there
was no statistically significant diabetes glucose
interaction. Nevertheless, whereas nondiabetic patients
with admission glucose levels >150 mg/dL (8.3 mmol/
L) were at significantly higher than minimum risk, which
corresponded to a level of 110 mg/dL (6.1 mmol/L)
(Figure 2, A), for patients with known diabetes there was
again no level that was associated with a significantly
higher risk of death (Figure 2, B).
Comparison of admission and fasting glucose for
predicting short- and long-term mortality
Among patients without known diabetes, the AUC(t)
curves for both admission and fasting glucose showed
sharp initial peaks of around 0.8, as did the curve for
fasting glucose among known diabetic patients. Subsequently, the AUC(t) values for the 2 glucose parameters
were similar among nondiabetic patients for forecast
times up to rather longer than 1 year and, in both cases,

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992 Cid-Alvarez et al

Figure 1

Nonparametric estimates of the dependence of all-time risk of death on fasting glucose among ACS patients without (A) and with (B) a prior
diagnosis of diabetes mellitus (log hazard ratio, with 95% confidence intervals; unadjusted analyses). Ref, reference values. To convert mg/dL of
glucose to mmol/L, divide by 18.

tended to fall gradually from nearly 0.7 to around 0.65

(Figure 3, A); for longer forecast times, however, the AUC
for fasting glucose tended to rise again towards 0.7,
whereas the AUC for admission glucose fell <0.6, the
difference being statistically significant (P < .05) for times
longer than 2.5 years (Figure 3, C). Among known
diabetic patients, neither admission glucose nor fasting
glucose afforded, at any time after the first few days, an
ROC with an AUC larger than 0.6 (Figure 3, B and D).

Multivariate analysis
The J-shaped relationship between fasting glucose
levels and log hazard ratio among non-diabetic patients
persisted after controlling for confounding factors: least
hazard was associated with fasting glucose levels of

around 110 mg/dL (6.1 mmol/L), and significantly greater

hazard at levels <90 mg/dL (5.0 mmol/L) or >119 mg/dL
(6.6 mmol/L) (Figure 4). The other significant independent predictors of mortality identified were age, smoking,
STEMI, anemia, and a Killip class 2. (Table III).

Discussion
The above results show that in our population neither
admission nor fasting glucose is predictive of all-cause
mortality among ACS patients with known diabetes.
However, among ACS patients without a prior diagnosis
of diabetes unadjusted risk is significantly greater than
minimum for admission glucose levels >150 mg/dL
(8.3 mmol/L); and as fasting glucose deviates in either

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Cid-Alvarez et al 993

Figure 2

Nonparametric estimates of the dependence of all-time risk of death on admission glucose among ACS patients without (A) and with (B) a prior
diagnosis of diabetes mellitus (log hazard ratio, with 95% confidence bands; unadjusted analyses).

direction from its minimum-risk value (110 mg/dL,

6.1 mmol/L) risk increases significantly even when
other risk factors are taken into account. The predictive
utilities of fasting glucose and admission glucose, as
evaluated by the areas under time-dependent ROCs, are
similar for forecast times of up to about 1 year, but fasting
glucose is significantly more valuable for forecast times
longer than about 2.5 years.
Numerous previous studies have investigated the
utility of blood glucose for prognosis among diabetic
and/or nondiabetic patients following acute coronary
events,1,3-15,20,21 and most of those that have included
both patients with and patients without known
diabetes have found, like the present study, that
blood glucose level has greater prognostic value for
the latter.4,9,10,12,15 For example, Aronson et al.

reported that among 462 diabetic and 1101 nondiabetic patients followed up for a median 24 months,
fasting glucose was only associated with increased risk
of death in the non-diabetic group, in which its
prognostic value was additional to that of the GRACE
risk score and left ventricular ejection fraction.15
Almost all the studies cited above distinguished only
between normal glucose levels and 1 levels of hyperglycemia. However, Svensson et al11 reported that among
diabetic patients a hypoglycemic lowest inhospital glucose
value was also associated with worse adjusted all-cause 2year mortality risk, and Kosiborod et al10 that hypoglycemic mean glucose was likewise associated with increased
inhospital mortality, while Pinto et al. obtained similar
results for admission glucose as regards 30-day mortality.20
The present study found that both hypoglycemic and

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December 2009

Forecast time dependence of the AUC for glucose-based prediction of all-cause mortality among ACS patients without (A) and with (B) a prior diagnosis of diabetes mellitus. Continuous lines, based
on admission glucose; dotted lines, based on fasting glucose. Panels C (for nondiabetic patients) and D (for diabetic patients) show the difference between AUCs based on fasting and admission
glucose, with the corresponding 95% confidence bands.

994 Cid-Alvarez et al

Figure 3

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Cid-Alvarez et al 995

Figure 4

Nonparametric estimates of the dependence of all-time risk of death on fasting glucose among ACS patients without a prior diagnosis of diabetes
mellitus, after controlling for potential confounding variables (log hazard ratio, with 95% confidence band; adjusted analysis).

Table III. Cox adjusted hazard ratios for all-cause death during
the 4-year duration of the study among patients with no prior
diagnosis of diabetes

Age, y
Female sex
Hypertension
Smoking
Prior CAD
STEMI
Coronary angiography
Killip 2
Creatinine, mg/dL
Anemia
Fasting glucose, mg/dL (mmol/L)
66 (3.6)
74 (4.1)
90 (5.0)
110 (6.1) (reference level)
119 (6.6)
150 (8.3)
175 (9.7)
200 (11.1)

HR

95% CI

1.07
1.28
0.90
2.01
1.51
2.37
0.65
2.34
1.23
1.76

1.04-1.10
0.70-2.36
0.53-1.50
1.13-3.57
0.90-2.53
1.42-3.96
0.40-1.06
1.42-3.86
0.82-1.84
1.03-2.53

<.001
.420
.630
.018
.112
<.001
.087
<.001
.310
.037
<.001

2.61
2.87
1.79
1.00
1.11
2.21
3.52
5.21

0.55-12.4
1.18-6.98
1.00-3.20
1.02-1.20
1.49-3.28
1.97-6.31
2.57-10.5

The final model included all variables listed above, risk from fasting glucose being
modelled by means of natural splines (see Methods; by way of illustration, results are
listed here for eight fasting glucose values). CAD: coronary artery disease.

hyperglycemic values of fasting glucose were predictive of

all-time mortality among non-diabetic patients, and neither
among diabetic patients.
Whether hypo- and hyperglycemia are mediators or
merely markers of adverse outcomes remains unclear.
That hypoglycemia may precipitate or increase myocar-

dial ischemia in diabetic patients is suggested by the

results of two small studies: in one, ischemia-related ECG
changes were associated with insulin-induced hypoglycemia in the presence of coronary disease,22 and in the
other hypoglycemia detected by continuous glucose
monitoring correlated with the presence of angina and
ischemia-related changes in ambulatory ECG records.23
These possible effects of hypoglycemia may be due to its
being associated with raised catecholamine levels and
decreased serum potassium,22 both of which are
associated with adverse cardiac outcome in ACS
patients.24 In non-diabetic patients, hypoglycemia may
be just a marker of the severity of background disease
such as abnormal liver function, congestive heart failure,
shock, occult malignancies, renal failure, or other clinical
conditions that adversely influence outcomes.25 However, as Table III shows, in this study hypoglycemic fasting
glucose levels continued to indicate significantly greater
risk than the reference level after adjustment for potential
confounding factors.
Elevated glucose levels during ACS may reflect high
levels of catecholamines, cortisol, and other factors that
are associated with the severity of ischemic disease.14,26,27 Elevated glucose has also been associated
with higher free fatty acid levels,28 reduced insulin
sensitivity, and impaired myocardial glucose use resulting
in increased oxygen consumption and potential worsening of ischemia29there have been reports of hyperglycemia being associated with marked reduction in
coronary flow reserve.30,31
The observed influence of diabetes status on the
relationship between blood glucose and mortality may

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996 Cid-Alvarez et al

derive from at least two factors. Firstly, a proportion of

hyperglycemic ACS patients with no previous diagnosis
of diabetes25% to 70% according to some estimates32,33are in fact diabetic patients; because these
patients usually fail to receive insulin or other treatment
appropriate for diabetic ACS patients upon admission,
they may constitute a group with especially high shortterm risk.34 Secondly, a given hyperglycemic blood
glucose level implies a greater surge in blood glucose in
a truly nondiabetic patient than in a diabetic patient,
which suggests a higher degree of stress and hence
greater risk of death.9
Relatively few previous studies have compared the
prognostic utility of admission glucose with that of the
first postadmission fasting glucose measurement or some
kind of average fasting glucose measure.7,10,21 Most of
those that have, have found that fasting glucose is the
better predictor of inhospital or 30-day mortality, at least
among patients without previously diagnosed diabetes,
and this finding appears to be independent of the therapy
received in hospital.7,10,21 In the present study, the AUC
of fasting glucose among non-diabetic patients tended to
be larger than that of admission glucose during this early
postinfarct period, but the small number of deaths meant
that the difference was not statistically significant. In
terms of AUC, both glucose parameters performed much
better in predicting deaths within the first few days postinfarct than for any longer forecast time, doubtless due to
the more immediate relationship between acute stress
and risk of death. As noted above, in this study, the
difference between the AUCs of fasting and admission
glucose was statistically significant, in favor of the former,
for forecast times longer than about 2.5 years. Thus,
admission glucose appears to be primarily a marker of
early risk, reflecting, at least in part, differences in stressinduced insulin resistance, etc., due to differences in
infarct size and/or hemodynamic compromise.2,14 The
greater ability of fasting glucose to predict long-term risk
may be due to its being more related to the patient's
background metabolic state.15

Study limitations
This study concerned the risk of all-cause mortality
conditional on serum glucose levels measured in a sample
taken at admission and a second sample obtained, within
24 hours of the first, after an overnight fast of >8 hours.
We were not in a position to determine how many
patients had persistent hyper- or hypoglycemia during
hospitalization, or whether deaths were the consequence
of ACS. The observational nature of the study also means
that it does not show whether hyper- and/or hypoglycemia were causally linked to adverse outcome, were
simply markers of greater disease severity, or both.
Moreover, it does not allow the possibility of confounding
due to unmeasured factors to be ruled out. However, as

circumstances tending to minimize this possibility we

note that the sample was large (811 patients) and
excluded no ACS patients seen in our centre during the
study period; that data collection was prospective; and
that all the patients in the sample were followed up
successfully. Furthermore, the observed relationships
between fasting glucose and all-time mortality persisted
after extensive adjustment for ACS severity and a number
of comorbidities.

Conclusions
Among patients who, at admission for ACS, are not
known to suffer diabetes, admission, and fasting plasma
glucose are both strong predictors of mortality. Likewise,
among nondiabetic patients, the predictive values of
admission and fasting glucose are similar for forecast
times of up to about 1 year, but the better predictor of longterm mortality is fasting glucose, for which the relationship
with the log hazard ratio of all-time mortality is J-shaped.
Neither admission nor fasting plasma glucose are useful in
our population for discriminating among known diabetic
patients as regards the risk of death after ACS.
According to our results, fasting glucose concentrations
in nondiabetic patients hospitalized for ACS may serve as
a simple marker to help clinicians stratify risk for optimal
triage and long-term surveillance and management.

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