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Review: Management of hyperglycaemia in acute coronary syndrome


Matthew J Devine, Wasala MHS Chandrasekara and Kevin J Hardy British Journal of Diabetes & Vascular Disease 2010 10: 59 DOI: 10.1177/1474651409357480 The online version of this article can be found at: http://dvd.sagepub.com/content/10/2/59

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Management of hyperglycaemia in acute coronary syndrome


MATTHEW J DEVINE,1 WASALA MHS CHANDRASEKARA,2 KEVIN J HARDY2
Abstract
o review the management of blood glucose in acute coronary syndrome (ACS) a literature search was undertaken using Medline and Embase databases (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 hyperglycaemia 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 criteria (two of which have yet to report). Only two of the remaining six trials reported that insulin therapy significantly reduces mortality in ACS patients with hyperglycaemia. 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 variability in management of blood glucose in ACS reflects a paucity of robust evidence to guide practice. Two ongoing 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

Abbreviations and acronyms ACC ACS AGE AHA AMI ATP CABG CHD CKMB CREATE DIGAMI ECLA FFA GKI HI-5 ICU IMMEDIATE INTENSIVE MI MINAP NHS NSTEMI Pol-GIK RCT SIGN American College of Cardiology acute coronary syndrome advanced glycation end products American Heart Association acute myocardial infarction adenosine triphosphate coronary artery bypass grafting coronary heart disease creatine kinase MB Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction Estudios Cardiolgicos Latinoamrica free fatty acids glucose-potassium-insulin Hyperglycemia: Intensive Insulin Infusion In Infarction intensive care unit Immediate Metabolic Myocardial Enhancement During Initial Assessment and Treatment in Emergency Care Intensive Insulin Therapy and Size of Infarct as a Validated Endpoint by Cardiac MRI myocardial infarction Myocardial Infarction National Audit Project National Health Service non ST-elevation myocardial infarction Polish Glucose-Insulin-Potassium randomised controlled trial Scottish Intercollegiate Guidelines Network

Introduction
Cardiovascular 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 estimated 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
1 2

School of Medical Education, University of Liverpool, Liverpool, UK. Diabetes 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: kevin.hardy@sthk.nhs.uk

characteristics of each element of the triad of clinical presentation, 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 dysglycaemia. 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,

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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 myocardial ischaemia. Insulin, either endogenous or exogenous, increases glucose utilisation and thereby reduces oxygen demand and myocardial damage.

a maximum blood glucose target of <180 mg/dL (10mmol/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 Hyperglycaemia


The pathophysiology of hyperglycaemia-associated myocardial damage is complex. Acute hyperglycaemia, similar to that observed in poorly controlled diabetic patients, produces haemodynamic changes and alters baroreflex activity via a glutathione-sensitive (presumably free radical-mediated) pathway.5 It also rapidly suppresses endothelium-dependent vasodilatation, probably through increased production of oxygen-derived free radicals.6 Reduced left ventricular function and cardiac arrhythmia has been described with hyperglycaemia.7,8 Biochemically, hyperglycaemia has been shown to affect immune markers of inflammation, intracellular adhesion molecules, and production of AGEs, which ultimately adversely affect cardiac outcomes. 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 approximately 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 associated 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 utilisation. 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 standardised in recent years. Glucose treatment remains an exception. Indeed, a recent observational study from the MINAP database showed that admission glucose was available in less than 30% of 190,000 ACS patients.11 The 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 infusion via an insulin pump and the remaining 4.6% received single-dose insulin regimens.11

Hypoglycaemia
In addition to hyperglycaemia, hypoglycaemia is also known to cause ischaemic myocardial damage through similar mechanisms to hyperglycaemia. The sympathetic response to hypoglycaemia, resulting in a substantial increase in plasma catecholamine levels, increases myocardial oxygen consumption 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 myocardial 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.10 recently reported that hypoglycaemia 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.

Glycaemia in non-ACS
Clinical trials conducted in non-ACS contexts suggest benefits from strict glycaemic control in patients with and without diabetes. 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).14 Van 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 three days. They randomised patients into intensive insulin treatment 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).15 Similarly,
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Guidelines
Current 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 recommended that 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 diabetes 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)

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a large trial in the USA studied continuous insulin infusion versus subcutaneous insulin in-patients with diabetes undergoing CABG.16 Continuous insulin infusion eliminated incremental increases in in-patient mortality following CABG associated with diabetes. A similar study carried out by Gandhi et al.17 in patients undergoing on-pump cardiac surgery, however, showed more deaths (p=0.061) and strokes (p=0.020) in an intensive insulin therapy group than a conventional treatment group (34). Limitations to this study include a relatively small number of patients involved in the study, using composite end points and the inability to examine whether outcomes differed by diabetes status. Other trials have also demonstrated the importance of glycaemic control for preventing postoperative wound infection in cardiac surgery.18,19 Overall present evidence supports that lowering blood glucose improves outcome in non-ACS patients.

DIGAMI-2 The DIGAMI-2 study aimed to resolve outstanding questions from the DIGAMI trial. Namely, whether beneficial effects seen in DIGAMI were due to insulin-glucose infusion or subsequent multi-dose insulin therapy or a mixture of the two. DIGAMI-2 was a multinational prospective randomised open trial, comparing three management strategies: (i) 24-h insulin-glucose infusion followed by long-term subcutaneous insulin, (ii) 24-h insulin-glucose infusion followed by standard glucose control, (iii) routine metabolic practice according to local protocol. Unfortunately, DIGAMI-2 failed to resolve the unanswered issues from DIGAMI. Blood glucose was significantly reduced in all groups after 24 h and mortality between groups 1 and 2 did not differ significantly (23.4% and 22.6% respectively; p=0.831). Mortality between groups 2 and 3 was also non-significant (22.6% and 19.3% respectively; p=0.203). ECLA The ECLA study, a pilot of 407 patients conducted in six Latin American countries, randomised participants with suspected AMI in a 2:1 ratio to intervention and control groups. The trial studied the effects of two interventions: (i) high-dose GKI infusion and (ii) low-dose GKI infusion. A significant reduction in mortality was demonstrated in patients in the GKI groups who received reperfusion therapy (5.2%, 95% CI 1.898.51) compared with similar control group patients (15.2%, 95% CI 7.2223.14) but numbers were small. CREATE-ECLA The CREATE-ECLA is an amalgamation of the ECLA and CREATE trials. The two trials were combined to produce a good study power. One part of the trial randomised patients to GKI infusion. This was a large 20,201 patient trial with only 20 lost to follow-up. The primary outcome was mortality in the GKI infusion and control groups at 30 days. There was no significant difference in mortality between the two groups (10% vs. 9.7%; GKI and control respectively, p=0.45). Moreover, there was no significant difference in the rates of cardiac arrest, cardiogenic shock, re-infarction or heart failure. The lack of benefit of GKI infusion was also apparent within the subgroups with or without diabetes. POL-GIK The POL-GIK study, a prospective multicentre randomised study consisted of 954 Polish patients with AMI randomised to low dose GIK (n=494) or to the control group (n=460). Cardiac mortality and the occurrence of cardiac events at 35 days did not differ between GIK and control-allocated patients (32 (6.5%) vs. 21 (4.6%) respectively, p=0.62). Total mortality at 35 days was significantly higher in the GIK than in the control group (44 (8.9%) vs. 22 (4.8%) respectively, p=0.01). The excess of noncardiac deaths in the GIK group may have occurred by chance. This study showed that low-dose GIK treatment does not improve the survival and clinical course in AMI.

Systematic literature review Literature selection


Trials were identified by searching English articles in Medline and Embase (1 January 195014 July 2008). The search strategy included the key terms diabetes mellitus or hyperglycaemia, 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 controls, (ii) were randomised, and (iii) assessed mortality and morbidity.

Results
Eight 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.13,21 The 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 diabetes. Patients (n=620) were randomised to standard therapy within a coronary care unit or standard therapy plus insulinglucose infusion for at least 24 h followed by transfer to multidose 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 significantly reduced mortality even during the hospital phase (relative reduction, 58%; p<0.05).

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Table 1. Summary of randomised controlled trials.

Trial DIGAMI13

Participants Men and women with AMI in the last 24 hours diabetes mellitus with a blood glucose

Follow-up and outcomes 3.4 years follow-up with mortality as the primary outcome.

Results Relative mortality reduction of 52% in the infusion group compared to the control group (p=0.046). At 1year the relative mortality reduction was still 52% (p=0.020). At 3.4 years follow-up the mortality reduction was 58% (p<0.05). Blood glucose was significantly reduced in groups 1 and 2 (9.1 and 9.1 mmol/L respectively) compared to group 3 (10.0 mmol/L). Mortality between groups 1 and 2 did not differ significantly (23.4 and 22.6% respectively). The mortality between groups 2 and 3 did not differ significantly either (22.6 and 19.3% respectively).

level > 11 mmol/L. Number of participants = 620, where 306 were randomised to the infusion group and 314 to the control group.

DIGAMI-220 ECLA CREATE- ECLA22


21

Men and women admitted to coronary care unit with suspected MI with a secondary diagnosis of type 2 diabetes mellitus or a blood glucose > 11 mmol/L. Number of participants = 1,253

Firstly comparing total mortality between groups 1 and 2. Secondly, comparing the total mortality between groups 2 and 3. Thirdly, comparing morbidity among the 3 groups.

where 474 were randomised to group 1 (insulin-glucose infusion AND subcutaneous insulin-based long term control), 473 to group 2 (insulin-glucose infusion + standard glucose control), and 306 to group 3 (routine metabolic management according to local practice). Men and women presenting with AMI within 24 hours of onset were included. Number of participants = 407, where 135 were randomised to high Trial focused on insulin without particular regard for glucose levels and measured mortality between GKI and control groups at 1-year follow-up.

61.9% of those treated with reperfusion strategies and randomised to the GKI groups had a significant reduction in mortality compared to the control (relative risk 0.34; 95% CI 0.150.78; p=0.008).

dose GKI infusion, 133 randomised to low dose GKI infusion and 139 randomised to the control group. Men and women presenting with ST-segment elevation AMI or new left bundle branch block within 12h of onset. Number of participants = 20,201, where 30-day follow-up looking at mortality differences between intervention and control groups. Secondary outcomes included rates of non-fatal cardiac arrest and cardiogenic shock.

There were no significant differences in mortality between the two groups. The rates of complication of treatment and non-fatal mortality were also similar. This showed a lack of benefit of GKI infusion on mortality, cardiac arrest and cardiogenic shock in patients with acute ST-elevated MI. (Continued)

10,091 were randomised to GKI infusion for 24 h + usual care and 10,110 were randomised to receive usual care alone.

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Table 1. (Continued)

Trial Pol-GIK23

Participants Men and women presenting with AMI within 24 h of onset were included. Number of participants = 954, where 494 were randomised to low dose

Follow-up and outcomes 35-day follow-up looking at cardiac mortality difference and occurrence of cardiac events between intervention and control groups.

Results There were no significant differences in cardiac mortality and occurrence of cardiac events between the two groups. There was excess of non-cardiac deaths in intervention group. This showed a lack of benefit in lowdose GKI infusion on mortality and cardiac events. Overall in-patient mortality was 4.1% and at 6 months 7.1%. There was no significant difference in mortality between the groups at in-patient stage (4.8% in insulin group and 3.5% in the conventional group, p=0.75). At 3-month and 6-month follow-up there was no significant difference either. There was, however, a lower incidence of heart failure (12.7 versus 22.8%, p=0.04) and re-infarction (2.4 versus 6.1%, p=0.05) in the insulin group. TRIAL ONGOING - RESULTS DUE IN 2012.

GKI and 460 randomised to control group.

HI-5
24

Men and women presenting with confirmed AMI within last 24 hours with a secondary diagnosis of diabetes mellitus or

Follow-up at 24 h, 3 months and 6 months comparing mortality between the 2 groups.

not diabetic with an admission blood glucose level of 7.8 mmol/L but less than 20 mmol/L. Number of participant = 240 (4 were excluded), where 126 were randomised to receive intensive insulin therapy and 114 were randomised to receive conventional therapy.

IMMEDIATE25 INTENSIVE
26

Study began in 2006 and is estimated to be completed in 2012 with an estimated enrolment of 15,450 patients. Patients > 30 years of age who present with ACS are randomised to receive either glucose-potassium-insulin infusion or intravenous dextrose for 12 hours. This trial will use magnetic resonance imaging to compare infarction size of patients with ST elevated AMI undergoing treatment with insulin glargine and insulin glulisine compared to usual care. Total number of patients anticipated is 700.

Primary outcome: Mortality at 30 days and 1 year. Secondary outcome: Heart failure or cardiac arrest.

Primary outcome: Comparison of MRI-determined infarction size between groups.

TRIAL ONGOING - RESULTS DUE IN 2010.

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 80mL/h or 10% dextrose at 40 mL/h for patients with cardiac failure. Patients randomised to the conventional therapy group received usual diabetes 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 subgroup 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 glycaemic 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-inflammatory effects, 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.

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 compared 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 significant benefit from insulin intervention. However, ECLA showed a statistically significant mortality reduction only in patients 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 glucose 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 infusioninduced 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 mortality 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 current practice is highly variable. IMMEDIATE and INTENSIVE are two trials currently investigating GKI and intensive insulin therapy respectively. Although testing two different hypotheses, certain aspects of the scientific rationale are common to both trials,27 and their results will hopefully better inform future practice.

Discussion
The six completed clinical trials study the effects of insulin treatment versus control in AMI patients presenting within 24 h. All

Conclusion
Hyperglycaemia is associated with a worse outcome in ACS and there is considerable variability in its management. Current

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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

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.

References
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13. Malmberg K, Ryden L, Efendic S et al. Randomised trial of insulin glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI Study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57-65. 14. Van Den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67. 15. Van den Berghe G, Wilmer A, Hermans G et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-61. 16. Furnary AP, Gao G, Grunkemeier GL et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125:1007-21. 17. Gandhi GY, Nuttall GA, Abel MD et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med 2007;146:233-43. 18. Golden SH, Camille PV, Kao WHL, Brancat F. Perioperative glycaemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care 1999;22:1408-14. 19. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352-62. 20. Malmberg K, Ryden L, Wedel H et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2); effects on mortality and morbidity. Eur Heart J 2005;26:650-61. 21. Diaz R, Paolasso EC, Piegas LS et al. Metabolic modulation of acute myocardial infarction: the ECLA glucose-insulin-potassium pilot trial. Circulation 1998;98:2227-34. 22. The CREATE-ECLA Trial Group Investigators: Effect of glucose-insulinpotassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction. JAMA 2005;293:437-46. ski L, Budaj A, Czepiel A et al. Low-dose glucose-insulin23. Ceremuzyn potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc Drugs Ther 1999; 13:185-9. 24. Cheung NW, Wong VW, McLean M. The Hyperglycaemia: Intensive Insulin infusion In Infarction (HI-5) Study: A randomised controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care 2006;29:765-70. 25. The Immediate Metabolic Myocardial Enhancement During Initial Assessment and Treatment in Emergency (IMMEDIATE) care study. www.clinicaltrials.gov/show/NCT00091507 (Accessed 14 July 2008). 26. INTENSIVE Trial. www.sanofi-aventis.ca/live/ca/medias/CC1E2A676117-4B3E-8077-7CD98621BD50.pdf (Accessed 14 July 2008). 27. Opie LH. Metabolic management of acute myocardial infarction comes to the fore and extends beyond control of hyperglycaemia. Circulation 2008;117:2172-7. 28. Diaz R, Goyal A, Mehta SR et al. Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction. JAMA 2007;298:2399-405. 29. Chaudhuri A, Miller M, Nesto R et al. Targeting glucose in acute myocardial infarction: has glucose, insulin, and potassium infusion missed the target? Diabetes Care 2007;30:3026-28.

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