Circulation Journal

Official Journal of the Japanese Circulation Society

REVIEW
http://www. j-circ.or.jp

Acute Hyperglycemia in Patients With

Acute Myocardial Infarction
Masaharu Ishihara, MD, PhD

Acute hyperglycemia is a common feature during the early phase after acute myocardial infarction (AMI), regardless
of diabetes status. Numerous studies have demonstrated that patients with AMI and hyperglycemia on admission
have high rates of mortality. It has been reported that there is a linear positive relation between admission blood
glucose levels and mortality after AMI. However, recent studies showed that the relationship is U-shaped in patients
with a history of diabetes. Diabetic patients with moderate hyperglycemia (glucose 9–11 mmol/L) had the lowest
mortality and not only severe hyperglycemia (glucose ≥11 mmol/L) but also euglycemia (glucose <7 mmol/L) was
associated with higher mortality. Although it has been debated whether acute hyperglycemia is causally related to
adverse outcomes after AMI or is simply an epiphenomenon of severely damaged myocardium, multiple physiolog-
ical studies have demonstrated that hyperglycemia has a direct detrimental effect on ischemic myocardium through
several mechanisms, including oxidative stress, inflammation, apoptosis, endothelial dysfunction, hypercoagulation,
platelet aggregation and impairment of ischemic preconditioning. Current guidelines recommend the use of an
insulin-based regimen to achieve and maintain glucose levels <10.0 mmol/dl, and emphasize the avoidance of
hypoglycemia. However, the optimal management goal of glucose levels for patients with acute hyperglycemia
remains uncertain. Further studies are warranted into the appropriate management in patients with AMI and acute
hyperglycemia.   (Circ J  2012; 76: 563 – 571)

Key Words: Diabetes mellitus; Glucose; Myocardial infarction

E
levation of blood glucose on admission (ie, acute hy-
perglycemia) is a common feature during the early
phase after acute myocardial infarction (AMI), even
in the absence of a history of diabetes mellitus.1 The relation-
ship between glycosuria and coronary thrombosis was dis-
cussed as early as 1931,2 and the prognostic value of the blood
glucose level in patients with AMI was first suggested in
1975.3 Since then, numerous studies have described the asso-
ciation between acute hyperglycemia and adverse outcome in
patients with AMI.4–8 Although it has been debated whether
acute hyperglycemia is causally related to adverse outcomes
after AMI or is simply an epiphenomenon of severely dam-
aged myocardium, multiple physiological studies have dem-
onstrated that hyperglycemia has a direct detrimental effect on
ischemic myocardium through several mechanisms. Although
hyperglycemia is usually managed with continuous insulin in-
fusion, the optimal management goal of the glucose level for
patients with acute hyperglycemia remains uncertain. This
review will provide an overview of the prevalence of acute
hyperglycemia, its relationship to outcomes, mechanisms of
the relationship and its treatment in patients with AMI.
Definition of Acute Hyperglycemia
Acute hyperglycemia is common among patients with AMI.
The prevalence of acute hyperglycemia in prior studies varies
from <10% to >80%.4 It mostly depends on the definition of
acute hyperglycemia, which is differs from study to study.
Threshold glucose concentration used to define acute hyper-
glycemia has ranged from 6.1 mmol/L (1 mmol/L=18 mg/dl)
to 11.0 mmol/L. As discussed later, there is a linear correlation
between the blood glucose level on admission and mortality
after AMI. Therefore, there is no clear cut-off value of blood
glucose to predict mortality and no consensus about the ap-
propriate definition of acute hyperglycemia for patients with
AMI. In most of the recent studies, 10.0 mmol/L or 11.0 mmol/L
of blood glucose on admission is used to define acute hyper-
glycemia.
Previous Studies Investigating the Relationship
Between Admission Glucose and
Mortality After AMI
In 2000, Capes et al performed a meta-analysis of 15 studies
reporting in-hospital mortality or congestive heart failure after

Received November 27, 2011; revised manuscript received January 9, 2012; accepted January 12, 2012; released online January 27, 2012
Department of Cardiology, Hiroshima City Hospital, Hiroshima, Japan
Mailing address:  Masaharu Ishihara, MD, PhD, FACC, Department of Cardiology, Hiroshima City Hospital, 7-33 Moto-machi, Naka-ku,
Hiroshima 730-8518 Japan.   E-mail: ishifami@fb3.so-net.ne.jp
ISSN-1346-9843   doi: 10.1253/circj.CJ-11-1376
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.76,  March  2012

564 ISHIHARA M

Figure 1.    In-hospital mortality rate in

relation to admission blood glucose
level: 2% in patients with glucose
≤5 mmol/L, 3% in patients with glu-
cose 5–7 mmol/L, 5% in patients with
glucose 7–9 mmol/L, 10% in patients
with glucose 9–11 mmol/L, 12% in
patients with glucose 11–13 mmol/L
and 18% in patients with glucose
>13 mmol/L; all P<0.001). Adapted
from reference 8 with permission.

Figure 2.    In-hospital mortality in pa-

tients with and without acute hyper-
glycemia defined as blood glucose
level on admission >11.0 mmol/L.
There was no significant difference
in mortality between patients with
and without diabetes. Adapted from
reference 8 with permission.

AMI in relation to blood glucose level on admission.4 When
patients did not have a history of diabetes, blood glucose on
admission ≥6.1–8.0 mmol/L was associated with a 3.9-fold
higher risk of death, and glucose >8.0–10.0 mmol/L with in-
creased risk of congestive heart failure or cardiogenic shock.
In patients with diabetes, blood glucose ≥10.0–11.0 mmol/L
was associated with a modestly increased risk of death, with
relative risk of 1.7. This meta-analysis, however, included
mostly older studies from the pre-reperfusion era or in the
thrombolysis era.
The Cooperative Cardiovascular Project is the largest study
to investigate the relationship between admission glucose level
and mortality after AMI.7 They reviewed 141,680 patients
aged ≥65 years with AMI, and showed that the 30-day and 1-
year mortality rates were linearly increased as the admission
blood glucose level increased. Interestingly, higher glucose
levels were associated with greater risk of mortality in patients
without known diabetes compared with diabetics. However,
that study included patients from 1994 to 1996, and most of
them did not receive reperfusion therapy. Thrombolysis was
performed in 18.2% and percutaneous coronary intervention
(PCI) only in 9.9%.
Findings From the Japanese Acute Coronary
Syndrome Study (JACSS)
JACSS is a retrospective and multicenter observational study
that finally included 5,325 consecutive patients hospitalized
within 48 h of the onset of AMI at 35 medical institutions
across Japan between 2001 and 2003.9 PCI was performed in
80% of the patients, mostly with stenting, and approximately
90% of the treated patients had successful coronary recanali-
zation during the acute phase of AMI. JACSS, reviewing
1,253 patients during the first year of the entry, first investi-
gated the clinical implication of the admission blood glucose
level on in-hospital outcomes in patients with AMI who were

Circulation Journal  Vol.76,  March  2012

Hyperglycemia and MI
Figure 3.    Relationship between admission blood glucose level and in-hospital mortality. It is near-linear in patients without diabe-
tes (blue circle) but U-shaped in patients with diabetes (red circle). Adapted from reference 11 with permission.
mostly treated with PCI.8 The major finding was that there was
a linear relation between blood glucose level on admission and
in-hospital mortality in the entire study group, including both
patients with and without diabetes (Figure 1). An increase of
1 mmol/L in blood glucose was associated with an increase in
mortality risk of 12% in the univariate analysis and 10% in the
multivariate analysis. In patients with acute hyperglycemia
that was defined as admission glucose >11.0 mmol/L had a
significantly higher in-hospital mortality than those without
(16% vs. 6%, P<0.001) (Figure 2). However, there was no
significant difference in mortality between patients with a
history of diabetes and those without (8% vs. 9%, P=0.54).
Although diabetes was shown to predict morbidity and mortal-
ity after AMI in the thrombolysis era, recent progress in the
treatment of patients with AMI has improved the short-term
outcome of diabetic patients. PCI is similarly successful in
diabetic and non-diabetic patients and is more effective than
thrombolytic therapy in diabetic patients with AMI. Indeed,
recent studies have reported that diabetes did not increase the
short-term mortality rate of patients with AMI undergoing
PCI, especially non-insulin-requiring patients with diabetes.
It is still debatable, however, that mortality rates are similar
between diabetic and non-diabetic patients, because acute hy-
perglycemia is more frequent in diabetic patients than in non-
diabetic patients.10 To clarify this issue, the influence of diabe-
tes status on the relationship between admission glucose and
mortality was investigated in 3,750 patients from JACSS.11 In
patients without a history of diabetes, there was a linear rela-
tion between admission blood glucose level and in-hospital
mortality, as in the original report (Figure 3). Non-diabetic
patients with glucose <6 mmol/L had the lowest mortality
(2.5%). As admission glucose increased by 1 mmol/L, mortal-
ity increased by 17% (P<0.001). In patients with a history
Circulation Journal  Vol.76,  March  2012
565
of diabetes, however, there was a U-shaped relationship be-
tween blood glucose level and mortality. Diabetic patients
with glucose 9–10 mmol/L had the lowest mortality (1.9%),
and not only severe hyperglycemia (glucose ≥11 mmol/L;
9.1%, P<0.001) but also euglycemia (glucose <7 mmol/L; 9.4%,
P=0.009) was associated with higher mortality as compared
with moderate hyperglycemia (glucose 9–11 mmol/L; 3.2%).
In patients with mild to moderate hyperglycemia, there was
no significant difference in the mortality of diabetic and non-
diabetic patients. However, when they had severe hypergly-
cemia on admission, in-hospital mortality was significantly
higher in patients without diabetes than in patients with diabe-
tes (P=0.02). As will be discussed later, acute fluctuation of
the blood glucose level increases oxidative stress, exaggerates
inflammation and promotes apoptosis. Because the blood glu-
cose level before AMI is usually higher in diabetic patients,
the threshold glucose level to induce such deteriorating effects
might have been increased. Another possible explanation is a
paradoxical resistance of diabetic hearts to ischemic chal-
lenge.12 It has been reported that the activity of the sodium
proton exchanger and calcium uptake, which play important
roles in reperfusion injury, are decreased in the diabetic heart.
Also, decreased glycolytic rates observed in diabetics lead to
less intracellular proton accumulation, which may be benefi-
cial to the heart, especially in circumstances of high plasma
glucose concentration.
Another important finding is that diabetes is associated with
significantly higher mortality not only in patients with severe
hyperglycemia but also in patients with euglycemia. The major
substrates of normal heart metabolism are glucose and free
fatty acids. Free fatty acids produce more adenosine triphos-
phate (ATP) per molecule but require more oxygen than glu-
cose. In the ischemic myocardium, where lack of oxygen in-
566 ISHIHARA M

Figure 4.    The 3-year mortality curves of diabetic patients with admission hyperglycemia (red solid line), non-diabetic patients with
admission hyperglycemia (blue solid line), diabetic patients without admission hyperglycemia (red dotted line) and non-diabetic
without admission hyperglycemia (blue dotted line). Non-diabetic patients without admission hyperglycemia had the lowest 3-year
mortality. There was no significant difference in the 3-year mortality among the remaining 3 groups. Adapted from reference 17
with permission.

duces a shift to anaerobic metabolism, glucose assumes a
central role for energy production. In the diabetic heart, how-
ever, uptake of glucose to myocytes, which is regulated by
glucose transporter, is impaired.13 Also, high levels of circulat-
ing and endogenous free fatty acids markedly decrease myo-
cardial glucose use.14 These changes may decrease the use of
glucose below a critical level necessary to maintain cellular
function, even with normal plasma glucose concentration and
increased rates of delivery of free fatty acids, which are poten-
tially harmful to the ischemic myocardium. In addition, dia-
betic patients with euglycemia may have a potential risk of
hypoglycemia. Although the precise mechanism remains un-
known, it is noteworthy that diabetic patients with euglycemia,
but not hypoglycemia, have a higher mortality rate than those
with mild to moderate hyperglycemia.
Different Influence of Acute Hyperglycemia
and Diabetes on Mortality After AMI
As discussed earlier, in the contemporary PCI era acute hyper-
glycemia is a predictor of short-term mortality after AMI, but
a history of diabetes is not. However, diabetes is still an im-
portant determinant of long-term outcomes in patients with
AMI.15,16 The influence of acute hyperglycemia and diabetes
on outcomes after AMI differs and is time dependent. My
group reviewed 802 consecutive patients with AMI who un-
derwent emergency coronary angiography at Hiroshima City
Hospital from 1996 to 2000 (Figure 4).17 PCI was performed
in 90% of the patients. Acute hyperglycemia was associated
with a significantly higher 30-day mortality rate (8.4% vs.
2.4%, P<0.001), but there was no significant difference in the
30-day mortality rate between diabetic and non-diabetic pa-
tients (5.7% vs. 3.9%, P=0.29). Conversely, diabetes signifi-
cantly increased mortality from 30 days to 3 years (10.0% vs.
5.5%, P=0.03), but acute hyperglycemia did not (8.4% vs.
5.9%, P=0.19). Acute hyperglycemia is associated with short-
term mortality, whereas diabetes increases long-term mortal-
ity after convalescence in patients with AMI.
Reviewing 4,176 patients without known diabetes undergo-
ing primary PCI for STEMI, Timmer et al recently reported
similar findings.18 Both elevated glucose and elevated HbA1c
levels measured on admission were associated with 1-year and
long-term mortality. An elevated glucose level, but not an
elevated HbA1c, was associated with larger infarct size. In turn,
HbA1c, but not glucose, was associated with long-term mortal-
ity after exclusion of early mortality (within 30 days) or after
multivariate analysis. Both the admission glucose and HbA1c
level reflect different patient populations, and their association
with outcome is related to different mechanisms.
Does Acute Hyperglycemia in Non-Diabetic
Patients Represent Previously
Undiagnosed Diabetes?
Abnormal glucose tolerance is common among patients with
AMI who have no previous diagnosis of diabetes. Norhammar
et al performed the oral glucose tolerance test (OGTT) in non-
diabetic patients with AMI at hospital discharge and showed
that 31% and 35% of the patients were diagnosed with diabe-
tes and impaired glucose tolerance (IGT), respectively.19 Some
previous investigators had confused acute hyperglycemia in
non-diabetic patients with previously undiagnosed diabetes,
and have regarded non-diabetic patients with acute hypergly-
cemia as having diabetes. To assess this issue, my group per-
formed the OGTT in 200 patients with AMI and no history of

Circulation Journal  Vol.76,  March  2012

Hyperglycemia and MI
diabetes.20 OGTT identified diabetes in 27% and IGT in 39%
of the patients. When patients were divided into 3 groups ac-
cording to blood glucose level on admission, the prevalence
of abnormal glucose tolerance was similar (Figure 5). The
relationship of fasting glucose (r2=0.50, P<0.001) and HbA1c
(r2=0.34, P<0.001) to 2-h post-load glucose was significant,
but there was no significant relation between admission glu-
cose and 2-h post-load glucose (r2=0.02, P=0.08). Therefore,
it is clear that acute hyperglycemia on admission in non-dia-
betic patients with AMI does not represent previously undiag-
nosed abnormal glucose tolerance.
Is Acute Hyperglycemia a Cause or
a Consequence of Severe Myocardial Damage?
Previous studies have clearly demonstrated that acute hyper-
glycemia is associated with higher mortality rates, larger infarct
size and impaired left ventricular (LV) function after AMI.
Circulation Journal  Vol.76,  March  2012
567
Figure 5.    Relationship between the
results of the oral glucose tolerance
test (OGTT) and admission blood glu-
cose level. Although diabetes was
most frequent in patients with admis-
sion glucose ≥11.1 mmol/L, impaired
glucose tolerance (IGT) was more fre-
quent in patients with lower admission
glucose. There was no significant dif-
ference in the prevalence of abnormal
glucose tolerance (diabetes or IGT)
among the 3 groups. Adapted from
reference 20 with permission.
Figure 6.    Acute hyperglycemia as-
sociated with both lower acute left
ventricular ejection fraction (LVEF)
and lower predischarge LVEF, but
the difference is more pronounced in
the latter. The change in LVEF was
significantly lower in patients with
acute hyperglycemia (red bars) than
in patients without (blue bars). Adapt-
ed from reference 21 with permis-
sion.
However, there is debate whether acute hyperglycemia is caus-
ally related to large infarct and impaired LV function after AMI
or is simply an epiphenomenon of the severe disease condi-
tions. Indeed, increased blood glucose level at admission is
associated with more comorbid factors, including higher Killip
class and large infarct. These findings suggest that hyperglyce-
mia may be at least in part a reflection of greater disease sever-
ity. To assess this issue, my group investigated the association
between acute hyperglycemia and LV function in 529 patients
with a first anterior wall AMI (Figure 6).21 Contrast Left ven-
triculography was performed before reperfusion therapy and
before hospital discharge. There was a small but significant
difference in acute LV ejection fraction (EF): patients with
acute hyperglycemia had lower LVEF before reperfusion
(46±12% vs. 48±10%, P=0.026). However, the difference was
more pronounced before hospital discharge. Patients with
acute hyperglycemia had a significantly lower predischarge
LVEF than those without (51±15% vs. 56%±15%, P=0.001).
568
Table.  Cardiovascular Effects of Acute Hyperglycemia
Oxidative stress
Inflammation
Apoptosis
Endothelial dysfunction
Hypercoagulability
Platelet hyperactivity
Impaired ischemic preconditioning
Impaired microcirculation
The improvement in LVEF was significantly smaller in pa-
tients with acute hyperglycemia (4.8±11.2% vs. 8.0±13.8%,
P=0.022). Multivariable analysis showed that there was a sig-
nificant correlation between higher glucose and impaired pre-
discharge LVEF, even after adjustment of acute LVEF. These
findings suggest that, although acute hyperglycemia is in part
a reflection of severely damaged myocardium at the time of
hospital admission, acute hyperglycemia is causally associated
with further deterioration of LV function after reperfusion.
Mechanisms by Which Acute Hyperglycemia
Exacerbates Myocardial Damage
Previous experimental and clinical studies have shown that
acute hyperglycemia causes several unfavorable effects that
contribute to the poor outcomes of patients with AMI (Table).
Oscillating hyperglycemia acutely increases oxidative stress
and exaggerates inflammation. Esposito et al22 measured cir-
culating levels of cytokines, including interleukin (IL)-6, IL-
18 and tumor necrosis factor-α in subjects with normal or IGT
during 3 consecutive pulses of intravenous glucose separated
by a 2-h interval. The plasma cytokine levels increased as the
blood glucose level increased but immediately returned to
normal as glucose returned to normal levels. Interestingly,
when the first elevation in the blood glucose level was main-
tained by subsequent continuous intravenous glucose infusion,
plasma cytokine concentrations gradually returned to normal
levels. Such responses of cytokines to acute elevation of blood
Circulation Journal  Vol.76,  March  2012
ISHIHARA M
glucose were completely prevented by an infusion of the anti-
oxidant glutathione. These findings suggest that acute hyper-
glycemia, not sustained elevation of the blood glucose level,
exaggerates inflammation by the oxidative mechanism.
Oscillating hyperglycemia also induces apoptosis of cells.
Risso et al reported that intermittent high glucose enhanced
apoptosis of human endothelial cells that were incubated in
media containing different glucose concentrations.23 Apopto-
sis, which was studied by viability assay, cell cycle analysis,
DNA fragmentation, and morphological analysis, was enhanced
in human umbilical vein endothelial cells exposed to intermit-
tent, rather than constant, high glucose concentrations.
Endothelial dysfunction is caused by acute hyperglycemia.
Williams et al24 assessed endothelium-dependent vasodilation
through brachial artery infusion of methacholine chloride in
non-diabetic subjects. They showed that hyperglycemia
significantly attenuated the forearm blood flow response to
methacholine, but did not reduce endothelium-independent
vasodilation to verapamil. Azuma et al reported that repetitive
fluctuations in blood glucose level enhanced monocyte adhe-
sion to the endothelium of rat thoracic aorta.25 Kersten et al
showed in a canine model that hyperglycemia decreases retro-
grade coronary collateral blood flow by adversely affecting
nitric oxide availability.26
Hyperglycemia also stimulates coagulation and platelet ag-
gregation. It has been reported that hyperglycemia elevates
coagulant activation markers, including thrombin antithrombin
complexes and soluble tissue factor, whereas hyperinsulinemia
inhibits fibrinolysis.27 Sakamoto et al28 examined alternation of
platelet aggregability during the OGTT. Platelet aggregability,
defined as the number of small platelet aggregations, was mea-
sured with a laser-light scattering method. During the OGTT,
platelet aggregability increased in parallel with the glucose
level. Small aggregates correlated positively with glucose lev-
els at 60 min post-load but not with insulin levels.
Hyperglycemia and Ischemic Preconditioning
Hyperglycemia also interferes with ischemic preconditioning.
Ischemic preconditioning is a potent endogenous cardioprotec-
tive mechanism that is promoted by the brief transient isch-
Figure 7.    In the absence of acute hy-
perglycemia, prodromal angina was
associated with preserved predis-
charge in left ventricular ejection frac-
tion (LVEF). Among patients with acute
hyperglycemia, there was no signifi-
cant difference in predischarge LVEF
between patients with (blue bars) and
without prodromal angina (red bars).
Adapted from reference 36 with per-
mission.
Hyperglycemia and MI
emia proceeding subsequent prolonged ischemia and reperfu-
sion. In 1986, Murry et al first showed in a canine model that
4 antecedent repetitive episodes of 5-min ischemia-reperfusion
resulted in a dramatic reduction in the infarct size from a sub-
sequent prolonged 40-min ischemia-reperfusion.29 In the clin-
ical setting, it has been demonstrated that prodromal angina
occurring shortly before the onset of AMI is associated with
smaller infarct size, preserved LV function and lower mortal-
ity after reperfusion therapy.30
Ischemic preconditioning delays infarct progression during
the early hours after the onset of AMI and extends the window
of time for reperfusion therapy.31 More importantly, ischemic
preconditioning decreases the extent of reperfusion injury.32,33
The molecular mechanism of ischemic preconditioning is com-
plex, but the mitochondrial KATP channels in myocytes play a
key role.34 Ischemia generates ATP, which activates the kinase
cascade and opens the KATP channels, which promotes cardio-
protection by inhibiting the mitochondrial permeability transi-
tion pore and other mechanisms. KATP channels also exist in the
pancreas where they are located in the surface of β-cells and are
open in the fasting state. Elevation of the glucose level closes
pancreatic KATP channels, which, by triggering molecular sig-
naling, regulates insulin release.35 Kersten et al have reported
in experimental models that acute hyperglycemia impairs the
activation of mitochondrial KATP channels and abolishes the
cardioprotective effect of ischemic preconditioning.36
My group assessed the influence of acute hyperglycemia on
the ischemic preconditioning effects of prodromal angina in
549 patients with a first anterior wall AMI.37 There was no
significant difference in the incidence of prodromal angina
between patients with acute hyperglycemia and patients with-
out. In patients without admission hyperglycemia, prodromal
angina was associated with preserved predischarge LVEF and
lower 30-day mortality (Figure 7). However, in patients with
admission hyperglycemia, such beneficial effects of prodro-
mal angina were completely abolished. These results suggest
that acute hyperglycemia prevents ischemic preconditioning
in patients with AMI undergoing reperfusion.
Inflammation, endothelial dysfunction, activated coagula-
tion, enhanced platelet aggregation and impairment of isch-
emic preconditioning directly damage the ischemic myocar-
dium. They also impair microvascular circulation and may
cause the no-reflow phenomenon during reperfusion. No-re-
flow phenomenon is associated with a large infarct and adverse
outcomes after AMI. JACSS reported that angiographic no-
reflow during PCI was more frequent in patients with acute
hyperglycemia.8 Using myocardial contrast echocardiography,
Iwakura et al showed that patients with the no-reflow phenom-
enon had significantly higher blood glucose levels on admis-
sion and that the blood glucose level was the strongest inde-
pendent predictor of the no-reflow phenomenon.38
Management of Acute Hyperglycemia
Among patients with AMI and acute hyperglycemia, persis-
tent hyperglycemia is associated with worse LV function and
higher mortality.39,40 Several studies have investigated whether
continuous insulin infusion to normalize the glucose level will
improve the outcome of patients with AMI.41 However, the
results have been inconsistent, and there is no consensus on
the safety and efficacy of glucose control using continuous
insulin infusion for patients with AMI. There are 2 major
questions about this issue. First, which of glucose control by
insulin infusion or metabolic modulation by glucose-insulin-
potassium (GIK) infusion is preferable for the management of
Circulation Journal  Vol.76,  March  2012
569
acute hyperglycemia in patients with AMI? Second, what is
the optimal management goal of the blood glucose level for
patients with AMI?
The Diabetes and Insulin-Glucose Infusion in Acute Myo-
cardial Infarction (DIGAMI) Study randomized 620 patients
with diabetes or admission glucose ≥11 mmol/L to ≥24-h insu-
lin-glucose infusion followed by subcutaneous insulin or rou-
tine antidiabetic therapy.42 Blood glucose levels were similar
before randomization, at approximately 15.5 mmol/L, and
became significantly lower in patients receiving the insulin-
glucose in fusion (9.6±3.3 mmol/L) than in the controls (11.7±
4.1 mmol/L, P<0.0001). Mortality during the 3.4 years was
33% in the insulin-glucose group and 44% in the control group
(P<0.011). The mortality reduction by insulin-glucose infu-
sion was most obvious in the highest tertile of baseline glucose
level (>16.5 mmol/L). In contrast, the Glucose-Insulin-Potas-
sium Infusion on Mortality in Patients With Acute ST-Seg-
ment Elevation Myocardial Infarction (CREATE-ECLA),
the largest scale international study that randomized 20,201
patients to GIK intravenous infusion for 24 h or usual care,
showed that high-dose GIK infusion had a neutral effect on
mortality, cardiac arrest, and cardiogenic shock in patients
with acute ST-elevation MI.43 The baseline blood glucose
level was 9.0 mmol/L, and most of the patients did not have
hyperglycemia. The dose of GIK infusion was fixed and hypo-
glycemia rarely occurred: only in 0.4% of the GIK group and
0.1% of the control group. By 24 h after randomization, the
mean glucose level was 8.6 mmol/L in the GIK group and
7.5 mmol/L in the control group. These 2 studies, as well as the
other previous studies, suggest that blood glucose control using
insulin, but not metabolic modulation by GIK, is important to
improve the outcomes of patients with AMI and acute hyper-
glycemia.
The second question is what is the optimal blood glucose
level for the management of patients with AMI and hypergly-
cemia? Prior guidelines, for example, the ACC/AHA Guide-
lines for the Management of Patients With ST-Elevation Myo-
cardial Infarction, until revised in 2009, recommended insulin
infusion to normalize blood glucose level in patients with ST-
elevation MI as Class I in patients with complicated course,
and Class IIa in patients without a complicated course.44 How-
ever, a recent meta-analysis of the 7 largest randomized trials,
including more than 11,000 patients, in 6 of which the target
glucose level was 80–110 mg/L, showed that intensive insulin
therapy provided no survival benefit, but rather was associated
with a higher incidence of hypoglycemia and increased mor-
bidity.45 Hypoglycemia triggers and deteriorates cardiovascu-
lar events by exaggerating inflammation.46 It also induces
increased platelet and neutrophil activation. The sympathetic
activation during hypoglycemia increases adrenaline secretion
that may induce arrhythmias and increase cardiac workload.
Underlying endothelial dysfunction leading to decreased vaso-
dilation may also contribute to cardiovascular risk. Desouza et
al reported, using continuous glucose monitoring, that hypo-
glycemia is more likely to be associated with cardiac isch-
emia than hyperglycemia in diabetic patients with coronary
artery disease.47 It has been shown that both hyperglycemia on
admission and hypoglycemia during hospitalization are inde-
pendently associated with mortality in diabetic patients with
acute coronary syndrome.48
The Normoglycemia in Intensive Care Evaluation-Survival
Using Glucose Algorithm Regulation (NICE-SUGAR) study
randomly assigned 6,104 patients admitted to the intensive
care unit (ICU) to undergo either intensive glucose control,
with a target blood glucose range of 4.5–6.0 mmol/L or con-
570
ventional glucose control, with a target of ≤10.0 mmol/L.49
The 90-day mortality was significantly higher in the intensive-
control group than in the conventional-control group (27.5%
vs. 24.9%, P=0.02). The difference in mortality between the 2
treatment groups was still significant after adjustment for the
predefined baseline risk factors (adjusted odds ratio, 1.14; 95%
confidence interval 1.01–1.29; P=0.04). Severe hypoglycemia
(defined as a blood glucose level ≤2.2 mmol/L) was recorded
more frequently in the intensive-control group. After these
studies, recent guidelines revised their recommendation from
intensive glucose control to mild glucose control, avoiding
hypoglycemia. The current AHA/ACC guideline was updated
in 2009 and recommends the use of an insulin-based regimen
to achieve and maintain a blood glucose level <10.0 mmol/dl,
avoiding hypoglycemia in patients with STEMI with either a
complicated or uncomplicated course.50 Similarly, the guide-
line from the American College of Physicians that was pub-
lished in 2011 recommends not using intensive insulin therapy
to strictly control blood glucose or to normalize blood glucose
in non-surgical or medical ICU patients with or without dia-
betes.51 It recommends a target blood glucose level of 7.8–
11.1 mmol/L if insulin therapy is used. However, there is no
clear evidence whether such target-driven glucose control in
AMI has meaningful clinical benefits.
Although continuous insulin infusion is the currently rec-
ommended first-line treatment for patients with AMI and acute
hyperglycemia, it takes time to achieve optimal glucose levels
by the time of reperfusion. Several adjunctive therapies to
reperfusion to limit infarct size have been investigated. Of
these, nicorandil, the only clinically available KATP opener, has
shown cardioprotective effects that mimic ischemic precondi-
tioning. Ishii et al randomized patients with AMI to intrave-
nous infusion of 12 mg nicorandil over 20 min just before PCI
or saline. They showed that intravenous nicorandil prevented
microvascular dysfunction, assessed by TIMI frame count and
ST-segment resolution, and improved event-free survival. These
beneficial effects of nicorandil were most pronounced among
patients with admission blood glucose level ≥10 mmol/L.52
Such adjunctive therapy may also be beneficial for patients
with AMI and acute hyperglycemia. Further studies are war-
ranted into the appropriate management in patients with AMI
and acute hyperglycemia.
Disclosures
There is no financial support for this study.
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