Diabetes and Cardiovascular Disease
Glucose-Lowering Targets for Patients With
Cardiovascular Disease
Focus on Inpatient Management of Patients With Acute Coronary Syndromes
Mikhail Kosiborod, MD; Darren K. McGuire, MD, MHSc
T he observation that elevated glucose levels can occur in
patients hospitalized with acute coronary syndromes
(ACS) was made many decades ago.1 Since then, a multitude
of studies have documented that hyperglycemia is common,
affects patients with and without established diabetes melli-
tus, and is associated with adverse outcomes, with a graded
increase in the risk of mortality and complications across the
spectrum of glucose elevations observed.2–26 However, a
number of critical gaps in knowledge remain. These include,
first and foremost, a better understanding of whether glucose
level is simply a risk marker of greater illness severity or a
risk factor with a direct causal relationship to the observed
adverse outcomes in patients with ACS. Similarly, it remains
unclear whether interventions to lower glucose in patients
with ACS (unstable angina, non–ST-segment elevation myo-
cardial infarction [MI], and ST-segment elevation MI) can
improve survival and other outcomes and, if so, what the
optimal targets, therapeutic strategies, and timing for such
interventions should be during ACS.
Downloaded from http://ahajournals.org by on November 26, 2023
In this article, we will review current knowledge about the
association between glucose levels and outcomes of patients
hospitalized with ACS; describe the available data with
regard to inpatient glucose management in patients with ACS,
as well as comparative data across the clinical spectrum of
critically ill hospitalized patients; address the controversies in
this field; and offer practical recommendations for patient
management based on the existing data.
Definition of Hyperglycemia in Patients
With ACS
Although hyperglycemia occurs commonly in hospitalized
patients with cardiovascular disease conditions other than
ACS, the relationship between glucose levels and outcomes
has not been well studied among those patient populations.
Therefore, the emphasis of this review will be on the care of
patients with ACS.
There is currently no uniform definition of hyperglycemia
in the setting of ACS. Prior studies used various hyperglyce-
mia cut points, ranging from ⱖ110 to ⱖ200 mg/dL.2 This is
compounded by different timing of glucose level assessments
From the Mid America Heart Institute of Saint Luke’s Hospital, Kansas City, MO (M.K.); University of Missouri–Kansas City (M.K.); and University
of Texas Southwestern Medical Center at Dallas (D.K.M.).
Correspondence to Mikhail Kosiborod, MD, Department of Medicine, Mid America Heart Institute of Saint Luke’s Hospital, 4401 Wornall Rd, Kansas
City, MO 64111. E-mail mkosiborod@cc-pc.com
(Circulation. 2010;122:2736-2744.)
© 2010 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
2736
in this context. Most prior studies defined hyperglycemia on
the basis of the first available (or “on-arrival”) glucose
value,2–11 whereas others used fasting glucose12–17 and glu-
cose values averaged over a period of time, such as the first
24 hours18 –20 or the entire duration of hospitalization.21
Recently, a random glucose level ⬎140 mg/dL observed at
any point over the course of ACS hospitalization has been
suggested as the definition of hyperglycemia in the American
Heart Association Scientific Statement on Hyperglycemia
and Acute Coronary Syndrome.22 This recommendation is
based, in part, on epidemiological studies demonstrating that
admission, mean 24-hour, and mean hospitalization glucose
levels above ⬇120 to 140 mg/dL are associated with in-
creased short-term mortality risk7,18,19,21 and that decline in
glucose levels below ⬇140 mg/dL during ACS hospitaliza-
tion is associated with better survival,23 although no cause-
and-effect conclusions can be drawn from these data because
of their observational nature.
However, the nature of the relationship between glucose
levels and short-term mortality differs in patients with and
without diabetes mellitus, with a paradoxically greater mag-
nitude of association in those without versus those with
prevalent diabetes mellitus.7,9,10,12,21,23 The risk of mortality
gradually rises when glucose levels exceed ⬇110 to 120
mg/dL in patients without diabetes mellitus, whereas in
patients with established diabetes mellitus, this risk does not
increase substantially until glucose levels exceed ⬇200 mg/
dL.7,21 Thus, different thresholds may be appropriate to define
hyperglycemia depending on the presence or absence of
known diabetes mellitus.
Prevalence of Elevated Glucose Levels in ACS
Numerous studies have documented that elevated glucose
occurs commonly in patients hospitalized with ACS.2–26
Although the definition of hyperglycemia varies across stud-
ies, the largest investigations show that the overall prevalence
of elevated glucose levels (⬎140 mg/dL) at the time of
hospital admission varies between 51% and 58%.7,21 Impor-
tantly, ⬎50% of patients with ACS who are hyperglycemic
on hospital arrival do not have known diabetes mellitus.7
DOI: 10.1161/CIRCULATIONAHA.109.913368
 Kosiborod and McGuire
Although glucose levels normalize in some ACS patients
after admission (either spontaneously or because of targeted
pharmacological interventions),24 the prevalence of persistent
hyperglycemia remains ⬎40% throughout the course of
hospitalization, and the prevalence of severe, sustained hy-
perglycemia (average hospitalization glucose ⬎200 mg/dL)
is ⬇14%.21,25 Although persistent hyperglycemia occurs
more commonly in patients with established diabetes mellitus
(78%) than in those without diabetes mellitus (26%),26 ⬎40%
of patients with persistent hyperglycemia do not have known
diabetes mellitus.21
Relationship Between Glucose Levels and
Mortality in ACS
Multiple studies have now proven a powerful, independent
relationship between elevated glucose and increased risk of
mortality and other adverse clinical outcomes in patients
hospitalized with ACS.2–26 Plausible pathophysiological un-
derpinnings potentially contributing to these observed asso-
ciations derive from a plethora of ex vivo animal and human
studies, which show that hyperglycemia may mediate adverse
effects on inflammation, cell injury, apoptosis, ischemic
myocardial metabolism, endothelial function, the coagulation
cascade, and platelet aggregation in the setting of acute
ischemia.22,27 The association between higher glucose and
greater mortality risk has been established across various
glucose metrics2–25 and across the spectrum of ACS3 and
applies to both short- and longer-term outcomes.7,21
The association between hyperglycemia and adverse out-
Downloaded from http://ahajournals.org by on November 26, 2023
comes among patients with ACS has been quantitatively
summarized on the basis of data from a large series of
relatively small human studies collected over a period of 3
decades by Capes et al.2 This systematic overview demon-
strated that among ACS patients without known diabetes
mellitus, the relative risk of in-hospital mortality was 3.9
times higher in those with initial glucose of ⱖ110 mg/dL
compared with normoglycemic patients (95% confidence
interval, 2.9 to 5.4). Among ACS patients with established
diabetes mellitus, those with initial glucose ⱖ180 mg/dL had
a 70% increase in the relative risk of in-hospital mortality
compared with normoglycemic patients. More recent studies
confirmed these findings and extended them across the
broader range of ACS to include ST-segment elevation MI,
non–ST-segment elevation MI, and unstable angina, demon-
strating a significant increase in the risk of short- and
long-term mortality, as well as incident heart failure, in
hyperglycemic ACS patients both with and without diabetes
mellitus.3,9,10 The largest observational study to date to
address this issue used the data from the Cooperative Car-
diovascular Project and showed a near-linear relationship
between higher admission glucose level and greater risk of
mortality at 30 days and at 1 year in ⬎140 000 patients
hospitalized with acute MI (AMI).7 A similar relationship
between elevated glucose and increased risk of death was also
shown with other glucose metrics, such as postadmission
fasting glucose,12,15–17 and with outcomes other than mortal-
ity, including such intermediates associated with adverse
clinical outcomes as “no-reflow phenomenon” after percuta-
Glucose Control in ACS 2737
Figure 1. Association between average blood glucose (BG) val-
ues and risk of in-hospital mortality. Reproduced from Kosi-
borod et al.21 with permission of the publisher. Copyright ©
2008, the American Heart Association.
neous coronary intervention28; greater infarct size7,21; worse
left ventricular systolic function5; and acute kidney injury.29
The association between hyperglycemia and increased risk
of death is not limited to the initial stages of ACS hospital-
ization. To the contrary, in a study of nearly 17 000 patients
hospitalized with AMI across 40 US hospitals, persistently
elevated glucose during hospitalization was a much better
discriminator of adverse events than was hyperglycemia on
admission (C statistic, 0.70 versus 0.62; P⬍0.0001).21 There
was a significant, gradual increase in the risk of in-hospital
mortality with rising mean hospitalization glucose levels
(Figure 1). Observational subanalyses of data from random-
ized clinical trials of glucose-insulin-potassium (GIK) ther-
apy and of targeted glucose control in ACS also confirm the
relationship between persistent hyperglycemia and increased
mortality risk.18,20
Another important observation is that the nature of the
relationship between higher glucose levels and increased
mortality is different in patients with and without established
diabetes mellitus.7,21 Regardless of the glucose metrics used,
the mortality risk starts rising at considerably lower glucose
levels and increases at a much steeper slope in patients
without known diabetes mellitus compared with those who
have previously diagnosed diabetes mellitus (Figure 1). This
phenomenon is incompletely understood, and several possible
explanations have been proposed. Many patients presenting
with hyperglycemia in the absence of previously diagnosed
diabetes mellitus actually have diabetes mellitus that simply
has not been recognized or treated before hospitalization,30
representing a higher-risk cohort because other undiagnosed
and untreated cardiovascular risk factors may be more prev-
alent in this group of patients. Moreover, although the effect
of targeted glucose control and insulin therapy in this clinical
setting remains uncertain, nondiabetic ACS patients with
hyperglycemia are less likely to be treated with insulin than
those with established diabetes mellitus, even when glucose
levels are markedly elevated.7,31 Further contributing to this
consistent observation is the fact that patients with estab-
lished diabetes mellitus tend to have clustering of numerous
risk factors contributing to clinical risk, which may attenuate
the magnitude of risk independently associated with any
 2738 Circulation December 21/28, 2010
Figure 2. Glucose normalization and survival during AMI hospi-
talization. Reproduced from Kosiborod et al24 with permission of
the publisher. Copyright © 2009, the American Medical
Association.
single factor, such as hyperglycemia. Finally, it is possible
that higher degrees of stress and illness severity are required
to produce similar degrees of hyperglycemia in patients
without known diabetes mellitus compared with those with
established diabetes mellitus.
Dynamic Changes in Glucose Levels During
ACS and Mortality
Adding to the growing body of data on the relationship
between hyperglycemia and adverse events in hospitalized
Downloaded from http://ahajournals.org by on November 26, 2023
ACS patients, several studies have shown that dynamic
changes in glucose values are also strongly associated with
patient survival. In post hoc analyses of data from the
Complement And ReDuction of INfarct size after Angio-
plasty or Lytics (CARDINAL) trial, a randomized clinical
trial that investigated the effect of a complement inhibitor,
pexelizumab, in 1903 patients with ST-segment elevation MI,
a decline in glucose of ⱖ30 mg/dL during the first 24 hours
of hospitalization was associated with lower risk of 30-day
mortality compared with the groups who had either no change
or an increase in glucose values.23 Similarly, in a study of
nearly 8000 patients hospitalized with ACS in the United
States who had hyperglycemia on arrival, glucose normaliza-
tion after admission was associated with better patient sur-
vival, even after adjustment for confounders (Figure 2).24
Although glucose normalization took place after insulin
administration in some patients, many patients experienced
normalization of their glucose values spontaneously (without
any glucose-lowering interventions). Interestingly, improved
survival was observed regardless of whether glucose normal-
ization occurred as the result of insulin therapy or happened
spontaneously. In fact, glucose normalization, and not insulin
therapy per se, was associated with better outcomes. From
these observational analyses, it remains unclear whether
normalization of glucose levels during hospitalization simply
identifies a lower-risk group of patients or reflects differences
in patient care or whether observed improvement in survival
is attributable in whole or in part to the lower glucose values
observed.
Clinical Trials of Glucose Control in Patients
With ACS
Although the strong relationship between elevated glucose
levels and greater risk of death in ACS is incontrovertible, a
critical question remains unanswered: Is hyperglycemia a
direct mediator of increased mortality and complications in
patients with ACS, or is it simply a marker of greater disease
severity and comorbidity? To definitively answer this ques-
tion, large randomized clinical trials of target-driven intensive
glucose control in hospitalized ACS patients are required.
Because no such clinical outcomes trial has been performed
to date, this issue continues to be highly controversial and
cannot be presently addressed with certainty. Nevertheless,
some insights may be gained from critical appraisal of a series
of small clinical trials of targeted glucose control in the ACS
setting, trials of GIK therapy that used a hyperinsulinemic,
hyperglycemic infusion strategy, and data from studies of
targeted glucose control conducted in non-ACS clinical
settings.
Because of marked variability in the insulin-infusion strat-
egies used and the hypotheses tested across the clinical trials
executed to date, one must first establish several key param-
eters to appropriately identify those randomized studies that
provide useful information with regard to the effect of
targeted glucose control in the ACS setting. These parameters
include the following: (1) the presence of hyperglycemia at
the time of patient randomization, with or without an ante-
cedent diabetes mellitus diagnosis (because targeted glucose
management is unlikely to yield benefit in the absence of
hyperglycemia); (2) target-driven glucose control as the
primary tested intervention, with substantially lower glucose
targets in the intervention versus control arm; (3) the achieve-
ment of a clinically and statistically significant difference in
glucose values between intervention and control groups after
randomization; and (4) the assessment of treatment effects on
meaningful patient outcomes as opposed to intermediate end
points.
To date, no ACS trial has fulfilled all of these criteria with
any degree of rigor. A few studies fulfilling some but not all
of these criteria are summarized in the Table. The trial most
closely satisfying the listed parameters is the Diabetes Mel-
litus, Insulin Glucose Infusion in Acute Myocardial Infarction
(DIGAMI) trial, with a number of key caveats in regard to its
interpretation.32,33 In DIGAMI, patients presenting within 24
hours of AMI symptoms with diabetes mellitus or initial
glucose levels ⬎198 mg/dL (11 mmol/L) were randomized to
a short- and longer-term insulin treatment regimen versus
usual care. Those randomized to the insulin arm received
ⱖ24 hours of intravenous dextrose-insulin infusion titrated to
maintain glucose levels of 126 to 180 mg/dL, initiated at 5
U/h of intravenous insulin in D5W, followed by subcutaneous
insulin injections 3 times daily for the subsequent 3 months
titrated to standard therapeutic targets for glucose control, to
be compared with usual care. The trial enrolled 620 patients,
80% of whom had previously diagnosed diabetes mellitus.
Admission glucose at study entry was 277 mg/dL in the
intervention group versus 283 mg/dL in the control group. By
24 hours, those randomized to the insulin arm achieved
significantly lower glucose levels compared with the control
 Kosiborod and McGuire
Table. Clinical Trials of Glucose Control in ACS
Targeted
Glucose Elevated Blood
Trial Control Glucose on Entry Glucose Targets Specified
DIGAMI (1995) ⫹/⫺ ⫹; ⬇280 mg/dL ⫹; 126 –180 mg/dL vs usual
care acutely, 90 –126 mg/dL
fasting blood glucose vs usual
care afterward
Pol-GIK (1999) ⫺ ⫺; 124 mg/dL ⫺ N/A; 106 vs 112 mg/dL in
DIGAMI2 (2005) ⫹/⫺ ⫹; 229 mg/dL ⫹; 126–180 mg/dL in-hospital
vs usual care acutely, 90–126
mg/dL fasting blood glucose
(group 1 only) vs usual care
afterward
CREATE-ECLA ⫺ ⫹; 162 mg/dL ⫺ N/A; glucose higher in intervention
(2005)
HI-5 (2006) ⫹/⫺ ⫹; ⬇198 mg/dL ⫹; 72–180 mg/dL vs usual
care
N/A indicates not applicable.
arm (173 versus 211 mg/dL; P⬍0.0001), although average
glucose values remained significantly elevated in both
groups; the differences between the groups were smaller by
hospital discharge but remained statistically significant (148
versus 162 mg/dL; P⬍0.01). Despite this early contrast in
glucose levels between the groups, no significant differences
in fasting glucose values were observed at any subsequent
Downloaded from http://ahajournals.org by on November 26, 2023
time point throughout the follow-up extending over 12
months from enrollment; however, HbA1C levels were sig-
nificantly lower in the intervention versus control group at 3
months (7.0% versus 7.5%; P⬍0.01). Also of note, hypogly-
cemia (not explicitly defined in the initial study reports) was
observed in 15% of the insulin infusion patients compared
with none in the usual care group, and this resulted in
discontinuation of the protocol treatment in 10% of partici-
pants. For the primary end point of all-cause mortality at 3
months, there was no significant difference between the
randomized groups (38 versus 49 deaths), with the respective
P value reported as not significant.32 Therefore, from a
“purist” perspective, based on failure to achieve statistical
significance in the primary end point, DIGAMI was a
negative trial. However, subsequent analyses of mortality at
both 1 year and 3.5 years of follow-up showed statistically
significant reductions in all-cause mortality in the insulin-
treated group.32,33 If one accepts the validity of the mortality
reduction observed in the longer-term analyses, the relative
contributions of the various aspects of the trial remain
uncertain, including (1) the effects of the short-term dextrose-
insulin infusion or (2) the effects of multidose insulin
injection in the outpatient setting. Therefore, although the
DIGAMI data are the most compelling in the field of targeted
glucose control for the treatment of ACS, the validity of the
observations and the relative attribution of improved survival
to short-term, in-hospital glucose lowering remain uncertain.
Beyond DIGAMI, a few other studies satisfy some (but not
all) of the proposed parameters of validity and generalizabil-
Glucose Control in ACS 2739
Clinical
End
Blood Glucose Contrast Achieved Points Results
⫹/⫺; 173 vs 211 mg/dL during ⫹ ⫹/⫺; mortality neutral at 3
first 24 h, difference in A1C but mo (primary end point),
not fasting blood glucose improved survival in glucose
afterward control arm by 1 y
⫹ Significantly higher mortality
intervention vs control arms in intervention vs control
arm at 35 d
⫹/⫺; 164 vs 180 mg/dL at 24 h, ⫹ ⫺; mortality neutral
no difference afterward between 3 groups
⫹ Mortality neutral
arm vs control (187 vs 148
mg/dL)
⫺; 149 vs 162 mg/dL (P⫽NS) ⫹ ⫺; mortality neutral
during first 24 h in-hospital, at 3 and 6 mo
ity with regard to targeted glycemic control in the ACS
setting. The Hyperglycemia: Intensive Insulin Infusion in
Infarction (HI-5) trial was designed to assess the effect of
dextrose-insulin infusion versus usual care in patients with
MI and hyperglycemia on arrival. Similar to DIGAMI, the
therapeutic target for the insulin arm was 72 to 180 mg/dL,
and intravenous dextrose (either D5W or D10W) was infused
with the insulin; however, the insulin dose was much lower in
HI-5 at 2 U/h (contrasted with 5 U/h used both in DIGAMI
and in most trials of GIK therapy).34 The HI-5 trial was
terminated early because of slow enrollment and failed to
achieve a statistically significant difference in glucose values
between the intensive and conventional glucose groups (149
versus 162 mg/dL 24 hours after randomization; P⫽NS).18
Mortality assessments at hospital discharge, 30 days, and 6
months all numerically favored usual care over targeted glucose
control with insulin treatment, although none of these compari-
sons were statistically significant because of very low numbers
of evaluable events (6 months, 10 versus 7 deaths; P⫽0.62).
The DIGAMI-2 multicenter study attempted to determine
whether potential survival benefit seen with targeted glucose
control in the original DIGAMI study was primarily attribut-
able to short-term or long-term glucose lowering with insu-
lin.35 In DIGAMI-2, 1253 patients with AMI and diabetes
mellitus or admission glucose ⬎198 mg/dL were randomized
to 1 of the 3 subgroups, as follows: (1) 24-hour insulin-
glucose infusion targeting glucose of 126 to 180 mg/dL,
followed by a subcutaneous insulin-based long-term glucose
control (group 1, identical to the original DIGAMI interven-
tion group); (2) same 24-hour insulin-glucose infusion but
followed by standard glucose control (group 2); and (3)
routine glucose management (group 3). Of note, the trial
planned to recruit 3000 patients and was stopped prematurely
because of slow recruitment. Glucose levels on arrival were
similar between the 3 arms (⬇229 mg/dL). At 24 hours after
randomization, glucose levels were modestly lower in the 2
 2740 Circulation December 21/28, 2010
groups assigned to short-term glucose lowering versus con-
trol (164 versus 180 mg/dL; P⬍0.01). This difference,
although statistically significant, was clinically small and
considerably less than expected; it was also much smaller
than that observed in the original DIGAMI study. There was
no difference in either glucose or HbA1C levels between the
3 groups at any other time point, with up to 3 years of
follow-up. Importantly, on average, patients in group 1 failed
to achieve the targeted fasting glucose range of 90 to 126
mg/dL during the outpatient management phase. Mortality
over 2 years was not statistically different between the 3
groups (23.4% versus 21.2% and 17.9% in groups 1, 2, and 3,
respectively; P⫽0.83 for group 1 versus group 2; P⫽0.16 for
group 1 versus group 3). Because of its limitations (primarily
lack of substantial contrast in glucose levels between the 3
groups), the DIGAMI-2 study did not provide a definitive
answer in regard to whether targeted glucose lowering
(whether short term or long term) has any clinical value in
patients with AMI.
The remaining trials evaluating the effects of insulin
infusion on clinical outcomes in the ACS setting have
predominantly tested the GIK hypothesis (ie, hyperinsu-
linemic, hyperglycemic therapy), as summarized in published
quantitative analyses,36 and have little to do with target-
driven glucose control. Studies like the Glucose-Insulin-
Potassium (GIPS) trial37 or the much larger Clinical Trial of
Reviparin and Metabolic Modulation in Acute Myocardial
Infarction Treatment and Evaluation–Estudios Cardiológicos
Latinoamérica (CREATE-ECLA) and the Organization for
Downloaded from http://ahajournals.org by on November 26, 2023
the Assessment of Strategies for Ischemic Syndromes
(OASIS)-6 trials (which in total randomized nearly 23 000
participants)19 assigned patients to fixed-dose GIK infusion
regardless of their initial glucose values or diabetes mellitus
status and did not prespecify targets for glucose control. In
these studies, as dictated by the infusion protocols, high-dose
delivery of insulin was supported by intravenous glucose
administration to affect modest hyperglycemia, defined by
protocol as a range of 126 to 198 mg/dL. For example, in the
CREATE-ECLA trial, which enrolled ⬎20 000 patients with
AMI and demonstrated no discernible treatment benefit with
GIK therapy,19 6-hour postrandomization glucose values
were significantly higher in the GIK group than in the control
group (187 versus 148 mg/dL). Thus, the GIK studies were
not designed to evaluate targeted glucose control with insulin,
and their findings should not be used in guiding decisions
about glucose management in ACS.
The Poland Glucose-Insulin-Potassium (Pol-GIK) trial ran-
domized 954 patients with AMI either to fixed “low-dose
GIK,” which included a much lower rate of insulin infusion
(0.8 to 1.3 U/h) than typical GIK regimens, or to normal
saline infusion.38 Although it was not a typical GIK trial in
that it used a much lower insulin dose, Pol-GIK cannot be
considered a study of targeted glucose control either. First, it
randomized patients who were on average normoglycemic at
study entry (initial glucose ⬇124 mg/dL in both groups). It is
therefore not entirely surprising that excess hypoglycemia
was observed in the intervention arm, which required lower-
ing of the fixed insulin dose during the conduct of the trial
from 1.3 to 0.8 U/h. Second, and similar to other GIK studies,
no glucose goals were prespecified or aimed for in this study,
and the dose of GIK infusion was fixed and not adjusted to
maintain a certain range of glucose values. As a result, there
was no significant difference in glucose levels 24 hours after
randomization (106 mg/dL in GIK versus 112 mg/dL in the
control arm). The study was stopped prematurely because of
excess mortality in the GIK arm at 35 days (8.9% versus 4.8%
in the control arm; P⫽0.01). However, because of the serious
limitations of interpretation stemming from the intent of the
trial to evaluate the effect of fixed-dose administration of
insulin rather than a targeted glucose control hypothesis, no
valuable lessons can be learned about glucose lowering and
patient outcomes in AMI on the basis of its results.
In summary, the clinical trial data for glucose control in
ACS are scarce and inconclusive. In this context, one might
be tempted to look for more definitive answers in the broader
critical care field of patients in other clinical settings. In 2001,
van den Berghe et al39 reported notable beneficial effects
associated with normalization of blood glucose using insulin
infusion compared with usual care among patients hospital-
ized in a surgical intensive care unit (ICU). These observa-
tions fueled enthusiasm among clinicians and professional
societies to endorse a strategy of targeted glucose control
across critically ill hospitalized populations.40 However, in
the 8 years that followed, several additional randomized trials
in various ICU patient populations have failed to reproduce
these beneficial results.41– 45 Key among these more recent
trials include the same investigators at the same institution
using the same protocol as the surgical ICU trial, testing
intensive glucose lowering in the medical ICU patients and
showing lower morbidity but no difference in the trial
primary end point of mortality with intensive glucose lower-
ing versus usual care.45 In addition, the Normoglycemia in
Intensive Care Evaluation–Survival Using Glucose Algo-
rithm Regulation (NICE-SUGAR) trial, which was the largest
trial of targeted glucose control in critically ill patients across
ICU settings, demonstrated significantly higher mortality
with intensive versus more conservative glucose control.42
These results have substantially tempered enthusiasm for
aggressive glucose lowering in the ICU setting. However, the
results of the NICE-SUGAR trial need to be interpreted in the
context of the study design; the NICE-SUGAR trial com-
pared “very intensive” glucose control with “good” glucose
control and not “usual care.” Specifically, an intravenous
insulin protocol was used in more than two thirds of patients
in the control arm, producing an average glucose level of
⬇142 mg/dL. This degree of glucose control is more inten-
sive than that achieved in control groups of other critical care
studies, is lower than that achieved in the intensive arm of
most ACS studies, and is much lower than that typically seen
in routine clinical care. Thus, the most appropriate conclusion
from the NICE-SUGAR study is that “good” glucose control
(with values somewhere between 140 and 180 mg/dL) is
sufficient, and more aggressive glucose lowering provides no
additive benefit and may even be harmful.
Extrapolation of observations from trials outside of the
ACS setting can also be problematic. Specifically, the find-
ings from patients hospitalized with surgical illness, trauma,
and sepsis cannot be simply extended to those with ACS. The
 Kosiborod and McGuire
pathophysiology of these conditions is different, and the
treatment thresholds and targets may be distinct as well. Prior
studies have shown that the relationship between glucose
values and mortality may vary significantly across various
cardiovascular conditions7,46; thus, it can also vary substan-
tially between cardiac and noncardiac disease states.
Ongoing Studies of Glucose Management
in ACS
Several clinical trials of glucose management in ACS are
currently ongoing. Although these studies may offer addi-
tional insights, they will not provide definitive answers in
regard to clinical effectiveness and safety of target-driven
glucose control in patients hospitalized with ACS.
The Immediate Myocardial Metabolic Enhancement During
Initial Assessment and Treatment in Emergency Care Trial
(IMMEDIATE) is a National Institutes of Health—sponsored,
randomized, placebo-controlled, double-blind, multicenter clin-
ical trial of GIK infusion (1.5 mL/kg per hour, continuous
infusion for total of 12 hours) administered as early as possible
in the setting of suspected ACS in the prehospital emergency
medical service setting.47 The primary hypothesis is that early
GIK administration will prevent or reduce the size of AMI.
Major secondary hypotheses are that GIK infusion will reduce
mortality (at 30 days and 1 year) and reduce prehospital or
in-hospital cardiac arrest and the propensity for heart failure. The
trial plans to enroll 880 patients by April 2011. IMMEDIATE is
specifically designed to test the GIK hypothesis and is not a
study of targeted glucose control in ACS. Similar to previous
Downloaded from http://ahajournals.org by on November 26, 2023
GIK trials, the presence of hyperglycemia is not required as an
inclusion criterion, and there are no prespecified goals for
glucose control.
The International Multicenter Randomized Controlled Trial of
Intensive Insulin Therapy Targeting Normoglycemia In Acute
Myocardial Infarction: REsearching Coronary REduction by
Appropriately Targeting Euglycemia (RECREATE) is an on-
going randomized, open-label pilot study of targeted glucose
control in patients with ST-segment elevation MI.48 Patients
presenting with an initial glucose value ⱖ144 mg/dL are
randomly assigned to either intensive glucose control or usual
care. Patients in the intensive arm are treated with intravenous
infusion of insulin glulisine for at least 24 hours and for as
long as coronary care unit–level care is required, with a target
glucose range of 90 to 118 mg/dL. Once transferred to the
ward, patients in the intensive arm are switched to insulin
glargine and continue this treatment for a total duration of 30
days after randomization. Patients in the control arm receive
usual care for AMI, according to the local practice of each
participating center. Because RECREATE is a pilot study
designed to demonstrate the feasibility of targeted glucose
control in ST-segment elevation MI, the primary end point is
24-hour difference in mean glucose between the 2 study
groups. Although a number of secondary efficacy and safety
end points will be explored (including all-cause and cardio-
vascular mortality, nonfatal recurrent MI, nonfatal stroke,
rehospitalization for heart failure, and hypoglycemia), the
study will likely lack statistical power to provide definitive
answers in regard to clinical outcomes. The RECREATE
Glucose Control in ACS 2741
Figure 3. Rates of treatment with any insulin in patients hospi-
talized with ACS across mean hospitalization glucose levels.
Adapted from Kosiborod et al.21
study is expected to recruit 500 patients and is planned to
finish enrollment in 2010.
Prognostic Importance of Hypoglycemia in
Patients With ACS
Because therapy of hyperglycemia in the hospital necessitates
the use of insulin, it is inevitable that glucose lowering in the
inpatient setting will produce excess hypoglycemia. Several
studies suggested that glucose values in the hypoglycemic
range may adversely affect mortality in ACS (93% increase
in the adjusted odds of 2-year mortality in 1 study)25,49 and
demonstrated a J-shaped relationship between average glu-
cose values during hospitalization and in-hospital mortality
(Figure 1).21 Whether hypoglycemia is directly harmful in
patients with ACS or whether it is simply a marker for the
most critically ill patients was recently evaluated in a large
observational study.50 The authors showed that the risk
associated with low blood glucose was confined to those who
developed hypoglycemia spontaneously, most likely as the
result of severe underlying illness. In contrast, hypoglycemia
that occurred after insulin initiation was not associated with
worse survival. Two subsequent analyses of data from the
DIGAMI-2 and CREATE-ECLA trials also found no signif-
icant association between hypoglycemia and mortality, after
adjustment for confounders.51,52 These findings suggest that
hypoglycemia is a marker of severe illness rather than a direct
cause of adverse outcomes. Although continuous efforts to
avoid hypoglycemia are certainly warranted, these studies
cast some doubt on the assumption that the lack of clinical
benefit from intensive glycemic control in clinical trials is
simply a consequence of excess hypoglycemia.
Current Patterns of Glucose Control in ACS
The current practice of glucose management in the United States
is highly variable.31 Large proportions of ACS patients with
hyperglycemia do not receive glucose-lowering therapy, even in
the setting of marked hyperglycemia (Figure 3); this is particu-
larly evident among those without known diabetes mellitus.7,26
A recent study from the United Kingdom showed that 64% of
patients without diabetes mellitus with admission glucose
 2742 Circulation December 21/28, 2010
ⱖ11 mmol/L (⬇200 mg/dL) received no glucose-lowering
treatments during hospitalization.53 Many factors contribute to
this inconsistency of clinical practice, such as the lack of
convincing clinical outcomes data, concerns about hypoglyce-
mia, institutional barriers, and clinical inertia, underscoring the
importance of continued investigation with regard to the efficacy
and safety of glucose management in the setting of ACS.
Summary and Recommendations
There is a clear and urgent need for well-designed, large-scale
clinical outcome trials of target-driven glucose control in ACS
with sufficient statistical power to detect a clinically important
difference in mortality and other adverse clinical outcomes.
Until such trials are completed, any specific recommendations in
regard to glucose management in ACS are based on epidemio-
logical observations, mechanistic hypotheses, and expert con-
sensus and are not grounded in solid clinical evidence.
Reflecting this uncertainty, in 2008 the American Heart
Association published an update on its position relative to
glucose targets for ACS/MI patients, which substantially
liberalized previous recommendations.22 This American
Heart Association position advocates for a glucose treatment
threshold of ⬎180 mg/dL. A similar position was adopted by
the 2009 focused update of ST-segment elevation MI guide-
lines54 and was also endorsed by the revised American
Association of Clinical Endocrinologists/American Diabetes
Association guidelines.55 These guidelines now recommend
the same glucose threshold for therapeutic intervention in
critically ill patients of ⬎180 mg/dL, with the suggested
Downloaded from http://ahajournals.org by on November 26, 2023
therapeutic target of glucose control specified at 140 to 180
mg/dL, a substantially more liberal approach than prior
documents.40 Although even these targets represent an expert
consensus, it is likely the most prudent approach in the
presence of the accumulated data.
Until more information becomes available, several practi-
cal suggestions are reasonable in regard to glucose manage-
ment during ACS hospitalization, as follows:
1. Assessment of glucose values at the time of admission and
glucose monitoring during hospitalization will provide
useful information in regard to risk stratification and
prognosis. Thus, it should be pursued regardless of
whether treatment is being considered.
2. If targeted glucose control is being considered, several
precautions should be observed:
a. Conservative treatment initiation thresholds and glu-
cose targets (as outlined above) should be used, in
agreement with the recommendations of professional
societies. Very aggressive glucose lowering, including
“normalization of blood glucose” as previously recom-
mended, does not clearly offer additional benefit and
may be harmful on the basis of existing data.
b. Evidence-based protocols should be used when and if
glucose control strategies are implemented. Such pro-
tocols should
i. have demonstrated effectiveness and safety with
regard to targeted glucose control in a variety of
clinical settings;
ii. incorporate the rate of change in glucose values as
well as insulin sensitivity in determination of
insulin infusion rates and adjustments;
iii. provide specific directions on the frequency of
glucose testing and hypoglycemia management.
3. Finally, and most importantly, continued efforts are nec-
essary for the design and execution of definitive clinical
trials assessing glucose control targets, therapies, and
timing so that more evidence-based recommendations
may be provided to clinicians in regard to glucose man-
agement during ACS.
Sources of Funding
Dr Kosiborod is supported in part by the American Heart Association
Career Development Award in Implementation Research.
Disclosures
Dr Kosiborod discloses a consultancy relationship with Medtronic
Minimed. Dr McGuire discloses consultancy relationships with
NovoNordisk, AstraZeneca, Roche, Daiichi-Sankyo, Tethys Bio-
science, and Biosite Inc.
References
1. Datey K, Nanda N. Hyperglycemia after acute myocardial infarction: its
relation to diabetes mellitus. N Engl J Med. 1967:262–265.
2. 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.
3. 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.
4. Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, Tor-
remocha F, Herpin D, Marechaud R. Prognostic value of admission
plasma glucose and HbA in acute myocardial infarction. Diabet Med.
2004;21:305–310.
5. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K,
Umemura T, Nakamura S, Yoshida M. Impact of acute hyperglycemia on
left ventricular function after reperfusion therapy in patients with a first
anterior wall acute myocardial infarction. Am Heart J. 2003;146:
674 – 678.
6. Kadri Z, Danchin N, Vaur L, Cottin Y, Gueret P, Zeller M, Lablanche JM,
Blanchard D, Hanania G, Genes N, Cambou JP. Major impact of
admission glycaemia on 30 day and one year mortality in non-diabetic
patients admitted for myocardial infarction: results from the nationwide
French USIC 2000 study. Heart. 2006;92:910 –915.
7. Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek
EP, Krumholz HM. Admission glucose and mortality in elderly patients
hospitalized with acute myocardial infarction: implications for patients
with and without recognized diabetes. Circulation. 2005;111:3078 –3086.
8. Meier JJ, Deifuss S, Klamann A, Launhardt V, Schmiegel WH, Nauck
MA. Plasma glucose at hospital admission and previous metabolic control
determine myocardial infarct size and survival in patients with and
without type 2 diabetes: the Langendreer Myocardial Infarction and
Blood Glucose in Diabetic Patients Assessment (LAMBDA). Diabetes
Care. 2005;28:2551–2553.
9. Stranders I, Diamant M, van Gelder RE, Spruijt HJ, Twisk JW, Heine RJ,
Visser FC. Admission blood glucose level as risk indicator of death after
myocardial infarction in patients with and without diabetes mellitus. Arch
Intern Med. 2004;164:982–988.
10. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. Is
blood glucose an independent predictor of mortality in acute myocardial
infarction in the thrombolytic era? J Am Coll Cardiol. 2002;40:
1748 –1754.
11. Yudkin JS, Oswald GA. Stress hyperglycemia and cause of death in
non-diabetic patients with myocardial infarction. BMJ (Clin Res Ed).
1987;294:773.
12. Aronson D, Hammerman H, Kapeliovich MR, Suleiman A, Agmon Y,
Beyar R, Markiewicz W, Suleiman M. Fasting glucose in acute myo-
cardial infarction: incremental value for long-term mortality and rela-
 Kosiborod and McGuire
tionship with left ventricular systolic function. Diabetes Care. 2007;30:
960 –966.
13. Mak KH, Mah PK, Tey BH, Sin FL, Chia G. Fasting blood sugar level:
a determinant for in-hospital outcome in patients with first myocardial
infarction and without glucose intolerance. Ann Acad Med Singapore.
1993;22:291–295.
14. 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.
15. Porter A, Assali AR, Zahalka A, Iakobishvili Z, Brosh D, Lev EI, Mager
A, Battler A, Kornowski R, Hasdai D. Impaired fasting glucose and
outcomes of ST-elevation acute coronary syndrome treated with primary
percutaneous intervention among patients without previously known
diabetes mellitus. Am Heart J. 2008;155:284 –289.
16. Suleiman M, Hammerman H, Boulos M, Kapeliovich MR, Suleiman A,
Agmon Y, Markiewicz W, Aronson D. Fasting glucose is an important
independent risk factor for 30-day mortality in patients with acute myo-
cardial infarction: a prospective study. Circulation. 2005;111:754 –760.
17. Verges B, Zeller M, Dentan G, Beer JC, Laurent Y, Janin-Manificat L,
Makki H, Wolf JE, Cottin Y. Impact of fasting glycemia on short-term
prognosis after acute myocardial infarction. J Clin Endocrinol Metab.
2007;92:2136 –2140.
18. Cheung NW, Wong VW, McLean M. The Hyperglycemia: Intensive
Insulin Infusion in Infarction (HI-5) study: a randomized controlled trial
of insulin infusion therapy for myocardial infarction. Diabetes Care.
2006;29:765–770.
19. Diaz R, Goyal A, Mehta SR, Afzal R, Xavier D, Pais P, Chrolavicius S,
Zhu J, Kazmi K, Liu L, Budaj A, Zubaid M, Avezum A, Ruda M, Yusuf
S. Glucose-insulin-potassium therapy in patients with ST-segment ele-
vation myocardial infarction. JAMA. 2007;298:2399 –2405.
20. Goyal A, Mehta SR, Gerstein HC, Diaz R, Afzal R, Xavier D, Zhu J, Pais
P, Lisheng L, Kazmi KA, Zubaid M, Piegas LS, Widimsky P, Budaj A,
Avezum A, Yusuf S. Glucose levels compared with diabetes history in the
risk assessment of patients with acute myocardial infarction. Am Heart J.
2009;157:763–770.
21. Kosiborod M, Inzucchi SE, Krumholz HM, Xiao L, Jones PG, Fiske S,
Downloaded from http://ahajournals.org by on November 26, 2023
Masoudi FA, Marso SP, Spertus JA. Glucometrics in patients hospitalized
with acute myocardial infarction: defining the optimal outcomes-based
measure of risk. Circulation. 2008;117:1018 –1027.
22. Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T,
Raskin P. Hyperglycemia and acute coronary syndrome: a scientific
statement from the American Heart Association Diabetes Committee of
the Council on Nutrition, Physical Activity, and Metabolism. Circulation.
2008;117:1610 –1619.
23. Goyal A, Mahaffey KW, Garg J, Nicolau JC, Hochman JS, Weaver WD,
Theroux P, Oliveira GB, Todaro TG, Mojcik CF, Armstrong PW,
Granger CB. Prognostic significance of the change in glucose level in the
first 24 h after acute myocardial infarction: results from the CARDINAL
study. Eur Heart J. 2006;27:1289 –1297.
24. Kosiborod M, Inzucchi SE, Krumholz HM, Masoudi FA, Goyal A, Xiao
L, Jones PG, Fiske S, Spertus JA. Glucose normalization and outcomes in
patients with acute myocardial infarction. Arch Intern Med. 2009;169:
438 – 446.
25. Svensson AM, McGuire DK, Abrahamsson P, Dellborg M. Association
between hyper- and hypoglycaemia and 2 year all-cause mortality risk in
diabetic patients with acute coronary events. Eur Heart J. 2005;26:
1255–1261.
26. Kosiborod M, Inzucchi S, Clark B, Krumholz H, Jones P, O’Keefe J,
Spertus J. National patterns of glucose control among patients hospi-
talized with acute myocardial infarction. J Am Coll Cardiol. 2007;49:
1018 –1183,1283A.
27. Marfella R, Di Filippo C, Portoghese M, Ferraraccio F, Rizzo MR,
Siniscalchi M, Musacchio E, D’Amico M, Rossi F, Paolisso G. Tight
glycemic control reduces heart inflammation and remodeling during acute
myocardial infarction in hyperglycemic patients. J Am Coll Cardiol.
2009;53:1425–1436.
28. Iwakura K, Ito H, Ikushima M, Kawano S, Okamura A, Asano K, Kuroda
T, Tanaka K, Masuyama T, Hori M, Fujii K. Association between hyper-
glycemia and the no-reflow phenomenon in patients with acute myo-
cardial infarction. J Am Coll Cardiol. 2003;41:1–7.
29. Kosiborod MMP, Rao S, Inzucchi SE, Maddox TM, Masoudi FA, Xiao
L, Fiske S, Spertus JA. Hyperglycemia and risk of acute kidney injury
after coronary angiography in patients hospitalized with acute myocardial
infarction. J Am Coll Cardiol. 2009;53:1028:A1382.
Glucose Control in ACS 2743
30. Conaway DG, O’Keefe JH, Reid KJ, Spertus J. Frequency of undi-
agnosed diabetes mellitus in patients with acute coronary syndrome. Am
J Cardiol. 2005;96:363–365.
31. Kosiborod M, Inzucchi S, Clark B, Krumholz H, Jones P, Spertus J.
Variability in the hospital use of insulin to control sustained hyper-
glycemia among acute myocardial infarction patients. J Am Coll Cardiol.
2007;49:1018 –1186,1284A.
32. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A,
Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed
by subcutaneous insulin treatment in diabetic patients with acute myo-
cardial infarction (DIGAMI study): effects on mortality at 1 year. J Am
Coll Cardiol. 1995;26:57– 65.
33. Malmberg K; DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in
Acute Myocardial Infarction) Study Group. Prospective randomised study
of intensive insulin treatment on long term survival after acute myocardial
infarction in patients with diabetes mellitus. BMJ. 1997;314:1512–1515.
34. Gnaim CI, McGuire DK. Glucose-insulin-potassium therapy for acute
myocardial infarction: what goes around comes around. Am Heart J.
2004;148:924 –930.
35. Malmberg K, Ryden L, Wedel H, Birkeland K, Bootsma A, Dickstein K,
Efendic S, Fisher M, Hamsten A, Herlitz J, Hildebrandt P, MacLeod K,
Laakso M, Torp-Pedersen C, Waldenstrom A. Intense metabolic control
by means of insulin in patients with diabetes mellitus and acute myo-
cardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur
Heart J. 2005;26:650 – 661.
36. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium in acute myo-
cardial infarction. Lancet. 1999;353:1968.
37. van der Horst IC, Zijlstra F, van’t Hof AW, Doggen CJ, de Boer MJ,
Suryapranata H, Hoorntje JC, Dambrink JH, Gans RO, Bilo HJ. Glucose-
insulin-potassium infusion inpatients treated with primary angioplasty for
acute myocardial infarction: the Glucose-Insulin-Potassium Study: a ran-
domized trial. J Am Coll Cardiol. 2003;42:784 –791.
38. Ceremuzynski L, Budaj A, Czepiel A, Burzykowski T, Achremczyk P,
Smielak-Korombel W, Maciejewicz J, Dziubinska J, Nartowicz E,
Kawka-Urbanek T, Piotrowski W, Hanzlik J, Cieslinski A, Kawecka-
Jaszcz K, Gessek J, Wrabec K. Low-dose glucose-insulin-potassium is
ineffective in acute myocardial infarction: results of a randomized mul-
ticenter Pol-GIK trial. Cardiovasc Drugs Ther. 1999;13:191–200.
39. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,
Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive
insulin therapy in the critically ill patients. N Engl J Med. 2001;345:
1359 –1367.
40. Garber AJ ME, Bransome ED, Clark NG, Clement S, Cobin RH, Furnary
AP, Hirsch IB, Levy P, Roberts R, Van den Berghe G, Zamudio V.
American College of Endocrinology position statement on inpatient
diabetes and metabolic control. Endocr Pract. 2004;10:77– 82.
41. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M,
Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D,
Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E,
Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K. Intensive
insulin therapy and pentastarch resuscitation in severe sepsis. N Engl
J Med. 2008;358:125–139.
42. Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R,
Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK,
McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J,
Robinson BG, Ronco JJ. Intensive versus conventional glucose control in
critically ill patients. N Engl J Med. 2009;360:1283–1297.
43. Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O’Brien PC,
Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA,
McMahon MM. Intensive intraoperative insulin therapy versus conven-
tional glucose management during cardiac surgery: a randomized trial.
Ann Intern Med. 2007;146:233–243.
44. Gray CS, Hildreth AJ, Sandercock PA, O’Connell JE, Johnston DE,
Cartlidge NE, Bamford JM, James OF, Alberti KG. Glucose-potassium-
insulin infusions in the management of post-stroke hyperglycaemia: the
UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 2007;6:
397– 406.
45. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ,
Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin
therapy in the medical ICU. N Engl J Med. 2006;354:449 – 461.
46. Kosiborod M, Inzucchi SE, Spertus JA, Wang Y, Masoudi FA, Havranek
EP, Krumholz HM. Elevated admission glucose and mortality in elderly
patients hospitalized with heart failure. Circulation. 2009;119:
1899 –1907.
 2744 Circulation December 21/28, 2010
47. IMMEDIATE Trial entry on the clinicaltrials.gov Web site. Available at:
http://www.clinicaltrials.gov/ct2/results?term⫽NCT00091507. Accessed
May 2, 2010.
48. RECREATE Trial entry on the clinicaltrials.gov Web site. Available at:
http://www.clinicaltrials.gov/ct2/results?term⫽NCT00640991. Accessed
May 2, 2010.
49. Pinto DS, Skolnick AH, Kirtane AJ, Murphy SA, Barron HV, Giugliano
RP, Cannon CP, Braunwald E, Gibson CM. U-shaped relationship of
blood glucose with adverse outcomes among patients with ST-segment
elevation myocardial infarction. J Am Coll Cardiol. 2005;46:178 –180.
50. Kosiborod M, Inzucchi SE, Goyal A, Krumholz HM, Masoudi FA, Xiao
L, Spertus JA. Relationship between spontaneous and iatrogenic hypo-
glycemia and mortality in patients hospitalized with acute myocardial
infarction. JAMA. 2009;301:1556 –1564.
51. Goyal A, Mehta SR, Diaz R, Gerstein HC, Afzal R, Xavier D, Liu L, Pais
P, Yusuf S. Differential clinical outcomes associated with hypoglycemia
and hyperglycemia in acute myocardial infarction. Circulation. 2009;120:
2429 –2437.
52. Mellbin LG, Malmberg K, Waldenstrom A, Wedel H, Ryden L. Prog-
nostic implications of hypoglycaemic episodes during hospitalisation for
myocardial infarction in patients with type 2 diabetes: a report from the
DIGAMI 2 trial. Heart. 2009;95:721–727.
Downloaded from http://ahajournals.org by on November 26, 2023
53. Weston C, Walker L, Birkhead J. Early impact of insulin treatment on
mortality for hyperglycaemic patients without known diabetes who pres-
ent with an acute coronary syndrome. Heart. 2007;93:1542–1546.
54. Kushner FG, Hand M, Smith SC Jr, King SB III, Anderson JL,
Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE Jr,
Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA,
Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams
DO. 2009 Focused updates: ACC/AHA guidelines for the management
of patients with ST-elevation myocardial infarction (updating the 2004
guideline and 2007 focused update) and ACC/AHA/SCAI guidelines
on percutaneous coronary intervention (updating the 2005 guideline
and 2007 focused update): a report of the American College of
Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Circulation. 2009;120:2271–2306.
55. Moghissi ES, Korytkowski MT, Dinardo M, Einhorn D, Hellman R,
Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE.
American Association of Clinical Endocrinologists and American
Diabetes Association consensus statement on inpatient glycemic control.
Endocr Pract. 2009;15:1–17.
KEY WORDS: diabetes mellitus 䡲 epidemiology 䡲 glucose 䡲 insulin 䡲
myocardial infarction