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The British Journal of Diabetes & Vascular

http://dvd.sagepub.com/content/10/2/59Theonline version of this article can be found at:

DOI: 10.1177/1474651409357480

2010 10: 59British Journal of Diabetes & Vascular DiseaseMatthew J Devine, WasalaMHS Chandrasekara and Kevin J Hardy

Review: Managementof hyperglycaemia in acute coronary syndrome

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Abstract

To review the management of blood glucose in

acute coronary syndrome (ACS) a literature search

was undertaken using Medlineand Embasedata-

bases (January 1950July 2008), bibliographies of

retrieved articles, review articles and Department of

Health reports. Trials were eligible for inclusion in the

review if they (i) included patients with ACS and hyper-

glycaemia with or without diabetes or compared insulin

infusion or glucose-potassium-insulin infusion with

active controls, (ii) were randomised, and (iii) assessed

mortality and morbidity. Eight trials met the above crite-

ria (two of which have yet to report). Only two of the

remaining six trials reported that insulin therapy signifi-

cantly reduces mortality in ACS patients with hypergly-

caemia. In conclusion ACS is of major public health

importance in the UK and hyperglycaemia in the setting

of ACS is associated with worse outcome. Current vari-

ability in management of blood glucose in ACS reflects a

paucity of robust evidence to guide practice. Two ongo-

ing trials may resolve the uncertainty about optimum

blood glucose management in ACS.

Br J Diabetes Vasc Dis 2010;10:5965.

Key words:acute coronary syndrome, diabetes, hyperglycaemia

IntroductionCardiovascular disease is the leading cause of premature

mortality in the UK and a public health priority for the NHS.1

Despite advances in primary and secondary preventative

strategies, there are 2.6 million people in the UK with CHD and

111,000 AMIs each year. Diabetes mellitus, which is a major

risk factor for CHD, has reached epidemic proportions. In the

UK, there are 2.35 million people with diabetes and an esti-

mated 1,300 new diagnoses each week.2

ACS describes a spectrum ranging from unstable angina to

AMI, with the definition of ACS depending on the specific

characteristics of each element of the triad of clinical presenta-

tion, electrocardiographic changes and biochemical cardiac

markers (Troponin T, Troponin I or CKMB). Approximately 20%

of patients presenting with AMI are known to have diabetes, but

another 30% have undiagnosed diabetes and 35% have

impaired glucose tolerance.3 Thus, approximately 85% of

patients who present with ACS have some degree of dysglycae-

mia. An increase of 1 mmol/L above normal blood glucose is

associated with an increase in mortality of 4% in non-diabetic

patients and 5% in known diabetic patients.4

During ACS, increased serum catecholamines, glucagon

and cortisol reduce insulin sensitivity and cause impaired

glucose utilisation and increased utilisation of fatty acids,

Management of hyperglycaemia in acutecoronary syndromeMATTHEW J DEVINE,1WASALA MHS CHANDRASEKARA,2KEVIN J HARDY2

The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651409357480 59

REVIEW

1School of Medical Education, University of Liverpool, Liverpool, UK.2Diabetes and Endocrinology, St Helens & Knowsley Teaching Hospitals,

St Helens Hospital, St Helens, Merseyside, UK.

Correspondence to: Dr K Hardy

St Helens & Knowsley Teaching Hospitals, St Helens Hospital, Marshalls

Cross Road, St Helens, Merseyside, WA9 3DA, UK.

Tel: +44(0)1744 646 499; Fax: +44(0)1744 646 491

E-mail: [email protected]

Abbreviations and acronyms

ACC American College of Cardiology

ACS acute coronary syndrome

AGE advanced glycation end products

AHA American Heart Association

AMI acute myocardial infarction

ATP adenosine triphosphate

CABG coronary artery bypass grafting

CHD coronary heart disease

CKMB creatine kinase MB

CREATE Clinical Trial of Reviparin and Metabolic Modulation

in Acute Myocardial Infarction Treatment Evaluation

DIGAMI Diabetes Mellitus Insulin-Glucose Infusion in Acute

Myocardial Infarction

ECLA Estudios Cardiolgicos Latinoamrica

FFA free fatty acids

GKI glucose-potassium-insulin

HI-5 Hyperglycemia: Intensive Insulin Infusion In

Infarction

ICU intensive care unit

IMMEDIATE Immediate Metabolic Myocardial Enhancement

During Initial Assessment and Treatment in

Emergency Care

INTENSIVE Intensive Insulin Therapy and Size of Infarct as a

Validated Endpoint by Cardiac MRI

MI myocardial infarction

MINAP Myocardial Infarction National Audit Project

NHS National Health Service

NSTEMI non ST-elevation myocardial infarction

Pol-GIK Polish Glucose-Insulin-Potassium

RCT randomised controlled trial

SIGN Scottish Intercollegiate Guidelines Network

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60 VOLUME 10 ISSUE 2 .MARCH/APRIL 2010

REVIEW

which unlike glucose metabolism requires oxygen. A shift from

using glucose to using more fatty acids during ACS therefore

increases myocardial oxygen demand and exacerbates myocar-

dial ischaemia. Insulin, either endogenous or exogenous,

increases glucose utilisation and thereby reduces oxygen

demand and myocardial damage.

HyperglycaemiaThe pathophysiology of hyperglycaemia-associated myocardial

damage is complex. Acute hyperglycaemia, similar to that

observed in poorly controlled diabetic patients, produces hae-

modynamic changes and alters baroreflex activity via a glutathi-

one-sensitive (presumably free radical-mediated) pathway.5 It

also rapidly suppresses endothelium-dependent vasodilatation,

probably through increased production of oxygen-derived free

radicals.6Reduced left ventricular function and cardiac arrhyth-

mia has been described with hyperglycaemia.7,8Biochemically,

hyperglycaemia has been shown to affect immune markers of

inflammation, intracellular adhesion molecules, and production

of AGEs, which ultimately adversely affect cardiac outcomes.

HypoglycaemiaIn addition to hyperglycaemia, hypoglycaemia is also known to

cause ischaemic myocardial damage through similar mecha-

nisms to hyperglycaemia. The sympathetic response to hypo-

glycaemia, resulting in a substantial increase in plasma

catecholamine levels, increases myocardial oxygen consump-

tion and simultaneously reduces myocardial oxygen supply by

coronary vasoconstriction. In addition, hypoglycaemia and

coronary vasoconstriction might limit the delivery of glucose

and free fatty acids to the myocardium, contributing to an

imbalance between myocardial energy supply and demand.

Libby et al.9

studied the effects of hypoglycaemia on myocar-dial ischaemic injury during acute experimental coronary artery

occlusion in dogs and showed that hypoglycaemia increases

myocardial damage, as reflected by enzymatic and histological

analysis. Kosiborod et al.10recently reported that hypoglycae-

mia was associated with increased mortality in patients with

AMI, but the risk was confined to patients who developed

hypoglycaemia spontaneously iatrogenic hypoglycaemia after

insulin therapy was not associated with higher mortality risk.

GuidelinesCurrent guidelines on management of ACS and AMI offer only

limited guidance on management of hyperglycaemia. SIGN 93

considered DIGAMI 1 and DIGAMI 2 and has recommendedthat marked hyperglycaemia in ACS (>11.0 mmol/L) should

have immediate intensive blood glucose control, continued for

at least 24 hours. The ACC-AHA guidelines on management of

unstable angina/NSTEMI recommend that all patients with dia-

betes and unstable angina/NSTEMI should have aggressive

glycaemic management in accordance with current standards

of diabetes care and this has been endorsed by the American

Diabetes Association and the American College of Endocrinology.

Their pre-prandial glucose target is < 110 mg/dL (< 6.1 mmol/L)

a maximum blood glucose target of < 180 mg/dL (10 mmol/L).

European Society of Cardiology guidelines on management of

AMI suggest to achieving glycated haemoglobin A1c< 6.5% in

diabetic patients. None of these guidelines recommends a best

method to achieve these glycaemic targets.

Glycaemia in ACS

Data from MINAP show that patients without known diabetes,presenting with ACS and admission glucose >11 mmol/L

treated with intravenous insulin have a mortality rate approxi-

mately 50% lower than similar patients not receiving insulin.11

Thus, contemporary evidence suggests that increased blood

glucose in acute MI patients with or without diabetes is associ-

ated with a worse outcome and that insulin treatment may be

associated with reduced mortality.12

Insulin infusion is currently used in patients with ACS either

to achieve intensive glycaemic control or co-administered with

glucose (GKI infusion) to modify myocardial substrate utilisa-

tion. The scientific rationale of GKI infusion is thought to derive

from its ability to improve the efficiency of myocardial energy

production and ventricular function as well as decrease free

fatty acids and ventricular arrhythmias.

Many aspects of the management of ACS have been stan-

dardised in recent years. Glucose treatment remains an excep-

tion. Indeed, a recent observational study from the MINAP

database showed that admission glucose was available in less

than 30% of 190,000 ACS patients.11The study also revealed

that definitions of what constituted raised blood sugar in ACS

were inconsistent and that glucose management varied from

nothing to aggressive use of intravenous insulin in the critical

care setting. In a subgroup of 872 patients receiving insulin,

69.6% received the insulin regimen described in an earlier

clinical trial (DIGAMI),13

25.8% received an intravenous infu-sion via an insulin pump and the remaining 4.6% received

single-dose insulin regimens.11

Glycaemia in non-ACSClinical trials conducted in non-ACS contexts suggest benefits

from strict glycaemic control in patients with and without dia-

betes. In the surgical intensive care unit, patients assigned to

intensive insulin therapy with the aim of maintaining blood

glucose below 6.2 mmol/L (110 mg/dL) had reduced morbidity

and mortality; overall in-hospital mortality was reduced by 34%

(p=0.01).14Van den Berghe et al.carried out a similar trial in

the medical intensive care unit which included 1,200 patients

who were considered to need intensive care for at least threedays. They randomised patients into intensive insulin treat-

ment arm (to maintain blood glucose 4.46.1 mmol/L) and

conventional insulin treatment arm (insulin administered when

blood glucose > 12.0 mmol/L). Results showed that there was

a significant reduction in morbidity in terms of prevention of

newly acquired kidney injury, accelerated weaning from

mechanical ventilation, and accelerated discharge from the

ICU and the hospital; however, there was an initial increased

mortality in the intensive treatment group (p=0.33).15Similarly,

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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 61

REVIEW

a large trial in the USA studied continuous insulin infusion

versus subcutaneous insulin in-patients with diabetes under-

going CABG.16 Continuous insulin infusion eliminated incre-

mental increases in in-patient mortality following CABG

associated with diabetes. A similar study carried out by Gandhi

et al.17in patients undergoing on-pump cardiac surgery, how-

ever, showed more deaths (p=0.061) and strokes (p=0.020) in

an intensive insulin therapy group than a conventional treat-ment group (34). Limitations to this study include a relatively

small number of patients involved in the study, using compos-

ite endpoints and the inability to examine whether outcomes

differed by diabetesstatus. Other trials have also demonstrated

the importance of glycaemic control for preventing post-

operative wound infection in cardiac surgery.18,19Overall pres-

ent evidence supports that lowering blood glucose improves

outcome in non-ACS patients.

Systematic literature reviewLiterature selectionTrials were identified by searching English articles in Medline

and Embase(1 January 195014 July 2008). The search strat-

egy included the key terms diabetes mellitus or hyperglycae-

mia, combined with acute coronary syndrome or myocardial

infarction and insulin. In addition, bibliographies of retrieved

trials, review articles and Department of Health reports were

reviewed. Limited data from unpublished trials were obtained

from investigators official websites.

Trials were eligible if they (i) included patients with ACS and

hyperglycaemia with or without diabetes or compared insulin

infusion or glucose-potassium-insulin infusion with active con-

trols, (ii) were randomised, and (iii) assessed mortality and

morbidity.

ResultsEight RCTs met all eligibility criteria (but IMMEDIATE and

INTENSIVE have yet to report their results). The eight studies are

summarised in table 1 and described below.13,20-26

DIGAMI

Insulin administration improving outcomes in ACS (particularly

AMI) is supported by two clinical trials from the 1990s.13,21The

DIGAMI multi-centre trial, conducted in 19 Swedish hospitals,

examined patients presenting with AMI and blood glucose

>11 mmol/L with or without an established diagnosis of diabe-

tes. Patients (n=620) were randomised to standard therapy

within a coronary care unit or standard therapy plus insulin-glucose infusion for at least 24 h followed by transfer to multi-

dose insulin therapy for a minimum of three months. One day

after randomisation, mean glucose concentrations were lower

in the infusion group (9.6 mmol/L) than the control group (11.7

mmol/L). At 3.4 years follow-up, there was a 28% reduction in

mortality in the infusion group compared with control. A group

of insulin nave patients at low cardiovascular risk had signifi-

cantly reduced mortality even during the hospital phase (rela-

tive reduction, 58%; p


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Table 1. Summary of randomised controlled trials.

Trial Participants Follow-up and outcomes Results

DIGAMI13 Men and women with AMI 3.4 years follow-up with Relative mortality reduction

in the last 24 hours diabetes mortality as the primary of 52% in the infusion group

mellitus with a blood glucose outcome. compared to the controllevel > 11 mmol/L. Number of group (p=0.046). At 1 year the

participants = 620, where 306 relative mortality reduction was

were randomised to the infusion still 52% (p=0.020). At 3.4

group and 314 to the control group. years follow-up the mortality

reduction was 58% (p 11 mmol/L. Number Thirdly, comparing morbidity Mortality between groups

of participants = 1,253 among the 3 groups. 1 and 2 did not differ

where 474 were randomised significantly (23.4 and 22.6%

to group 1 (insulin-glucose respectively). The mortality

infusion AND subcutaneous between groups 2 and 3 did

insulin-based long term control), not differ significantly either

473 to group 2 (insulin-glucose (22.6 and 19.3% respectively).

infusion + standard glucose control),

and 306 to group 3

(routine metabolic management

according to local practice).

ECLA21 Men and women presenting with Trial focused on insulin without 61.9% of those treated with

AMI within 24 hours of onset particular regard for glucose reperfusion strategies and

were included. Number of levels and measured mortality randomised to the GKI groups

participants = 407, where between GKI and control had a significant reduction in

135 were randomised to high groups at 1-year follow-up. mortality compared to the

dose GKI infusion, 133 randomised control (relative risk 0.34; 95%

to low dose GKI infusion and 139 CI 0.150.78; p=0.008).

randomised to the control group.

CREATE- Men and women presenting 30-day follow-up looking at There were no significant

ECLA22 with ST-segment elevation mortality differences between differences in mortality

AMI or new left bundle intervention and control groups. between the two groups.

branch block within 12 h of Secondary outcomes included The rates of complication of

onset. Number of rates of non-fatal cardiac arrest treatment and non-fatalparticipants = 20,201, where and cardiogenic shock. mortality were also similar.

10,091 were randomised to This showed a lack of benefit

GKI infusion for 24 h + usual of GKI infusion on mortality,

care and 10,110 were cardiac arrest and cardiogenic

randomised to receive shock in patients with acute

usual care alone. ST-elevated MI.

(Continued)



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Table 1. (Continued)

Trial Participants Follow-up and outcomes Results

Pol-GIK23 Men and women presenting 35-day follow-up looking at There were no significant

with AMI within 24 h of cardiac mortality difference differences in cardiac mortality

onset were included. Number of and occurrence of cardiac and occurrence of cardiacparticipants = 954, where 494 events between intervention events between the two

were randomised to low dose and control groups. groups. There was excess of

GKI and 460 randomised non-cardiac deaths in

to control group. intervention group. This

showed a lack of benefit in low-

dose GKI infusion on mortality

and cardiac events.

HI-524 Men and women presenting Follow-up at 24 h, 3 months Overall in-patient mortality was

with confirmed AMI within and 6 months comparing 4.1% and at 6 months 7.1%.

last 24 hours with a secondary mortality between the There was no significant

diagnosis of diabetes mellitus or 2 groups. difference in mortality between

not diabetic with an admission the groups at in-patient stage

blood glucose level of 7.8 mmol/L (4.8% in insulin group and

but less than 20 mmol/L. Number 3.5% in the conventional

of participant = 240 (4 were group, p=0.75). At 3-month

excluded), where 126 were and 6-month follow-up there

randomised to receive intensive was no significant difference

insulin therapy and 114 were either. There was, however, a

randomised to receive lower incidence of heart failure

conventional therapy. (12.7 versus 22.8%, p=0.04)

and re-infarction (2.4 versus

6.1%, p=0.05) in the insulin

group.

IMMEDIATE25 Study began in 2006 and is Primary outcome: Mortality at TRIAL ONGOING - RESULTS

estimated to be completed in 2012 30 days and 1 year. Secondary DUE IN 2012.

with an estimated enrolment of outcome: Heart failure or

15,450 patients. Patients > 30 years cardiac arrest.

of age who present with ACS are

randomised to receive either

glucose-potassium-insulin infusion

or intravenous dextrose for 12 hours.

INTENSIVE26 This trial will use magnetic resonance Primary outcome: Comparison TRIAL ONGOING - RESULTS

imaging to compare infarction size of of MRI-determined infarction DUE IN 2010.

patients with ST elevated AMI size between groups.undergoing treatment with insulin

glargine and insulin glulisine

compared to usual care. Total

number of patients

anticipated is 700.

Key:ACS = acute coronary syndrome; AMI = acute myocardial infarction; GKI = glucose-potassium-insulin, MI = myocardial infarction; MRI = magnetic

resonance imaging.



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HI-5

Like the DIGAMI studies, HI-5 aimed to evaluate whether strict

glucose control improves outcomes for AMI patients with

hyperglycaemia. Patients randomised to the insulin therapy

group were administered insulin at a variable rate (dependent

on blood glucose level) and 5% dextrose at 80 mL/h or 10%

dextrose at 40 mL/h for patients with cardiac failure. Patients

randomised to the conventional therapy group received usualdiabetes therapy plus supplemental subcutaneous insulin if

blood glucose levels exceeded 16 mmol/L.

The results showed a non-significant reduction in mortality

in the insulin therapy group at all stages of follow-up and sub-

group analysis demonstrated a lower infarction rate in patients

with diabetes at 3-month follow-up in the insulin therapy

group versus those on conventional therapy (0% vs. 7.7%

respectively; p=0.04). Similarly, a lower cardiac failure rate was

demonstrated in the insulin-treated patients without diabetes

(11.3% vs.27.4% respectively; p=0.02). Overall the results of

this study suggest that mean blood glucose is a predictor of

mortality in patients suffering AMI and therefore it remains

possible that strict glucose control with insulin therapy improves

outcome.

IMMEDIATE and INTENSIVE

Two ongoing trials are studying different hypotheses of glycae-

mic control in ACS.

The IMMEDIATE trial randomises patients presenting with

ACS to receive either GKI infusion or placebo infusion for 12 h.

This studys hypothesis is based on the following theory:27

Insulin may prevent ischaemia from developing into

infarction by promoting glycolytic flux leading to

membrane protection and increased ATP production. Insulin reduces oxidation of FFAs, which potentially

further damage the ischaemic myocardium.

Therefore high circulating glucose and insulin are both

required to maximise glycolytic flux.

Crucially, this studys design stipulates that intervention takes

place in the pre-hospital arena or on arrival at the emergency

department in an attempt to reduce myocyte death.25

The INTENSIVE trial studies patients presenting with an

anterior ST elevated MI with blood glucose > 7.7 mmol/L, who

are randomised to either intensive insulin therapy or standard

glycaemic care. The scientific rationale for this study is that

hyperglycaemia could have pro-oxidative and pro-inflammatoryeffects, which may lead to a worse outcome in AMI. Therefore,

normoglycaemia is the main aim of intensive insulin therapy in

this trial.27

The INTENSIVE trial will publish results in 2010 ahead of the

IMMEDIATE trial in 2012.

DiscussionThe six completed clinical trials study the effects of insulin treat-

ment versus control in AMI patients presenting within 24 h. All

trials used similar randomisation and follow-up and, with the

exception of ECLA, all had similar baseline characteristics

between intervention and control groups. Three trials com-

pared insulin-glucose with control.13,20,24 The remaining three

trials utilised GKI infusions.21,22,23

DIGAMI and ECLA were small trials that demonstrated sig-

nificant benefit from insulin intervention. However, ECLA

showed a statistically significant mortality reduction only inpatients who received concomitant reperfusion therapy and it

is not possible to determine whether the outcome in DIGAMI

is attributable to the insulin-glucose infusion, the subsequent

subcutaneous insulin therapy or a combination.

Neither DIGAMI-2 nor HI-5 recruited sufficient patients to

achieve predetermined power, which may have contributed to

their non-significant results. Moreover, adherence to insulin

was poor in DIGAMI-2, and prioritisation of other cardiac

therapies in HI-5, led to a mean 13-h delay from symptom

onset to insulin. DIGAMI-2 also failed to achieve adequate

separation of blood glucose control in the three arms and had

more hypoglycaemia in the intensive insulin therapy group and

most patients had better blood glucose control on admission to

DIGAMI-2 than to DIGAMI-1.

CREATE-ECLA was a large, well-executed trial with 99.85%

follow-up and a high study power, limited to patients with ST

elevation MI only. Unfortunately, blood glucose levels in the

intervention group were raised at 6 and 24 hours compared

with control, raising the question of whether high blood glu-

cose levels reduced the benefits of insulin.

Although three trials in this review utilise GKI infusions

without significant increase in heart failure, other studies raise

important questions regarding the safety of GKI.28,29 These

studies highlight the potential harm of GKI to cause infusion-

induced hyperglycaemia, hyperkalaemia and fluid overload.Fluid overload is particularly concerning because of the risk of

cardiac failure in this group of patients.

Thus, we can conclude that existing RCT evidence suggests

that hyperglycaemia in ACS adversely affects morbidity and mor-

tality and that it may be advisable to treat admission blood glucose

levels > 11.0 mmol/L irrespective of whether the patient has

known diabetes or newly detected hyperglycaemia. However,

existing RCT evidence is unclear about the precise benefits of

insulin treatment, the best method to administer insulin, optimum

duration of treatment and target blood glucose levels in ACS. This

insufficiency of good trial data makes it difficult to formulate a set

of evidence based guidelines and explains at least in part why cur-

rent practice is highly variable.IMMEDIATE and INTENSIVE are two trials currently investi-

gating GKI and intensive insulin therapy respectively. Although

testing two different hypotheses, certain aspects of the scien-

tific rationale are common to both trials,27and their results will

hopefully better inform future practice.

ConclusionHyperglycaemia is associated with a worse outcome in ACS

and there is considerable variability in its management. Current

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evidence that insulin therapy (intensive insulin therapy or GKI)

reduces mortality and morbidity in ACS is inconclusive, but may

be clarified by the results of the IMMEDIATE and INTENSIVE trials.

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Key messages

Hyperglycaemia is associated with a worse outcome in

ACS

Data are inconclusive for use of intensive insulin

therapy or GKI in ACS
http://dvd.sagepub.com/

management of hyperglycaemia in acute coronary syndrome.pdf

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