cme glu-acs

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Raffaele De Caterina, Rosalinda Madonna.European heart Journal 2010; 31: 1557-1564


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` The Euro Heart Survey on Diabetes and the

Heart1, and European Heart Journal data2indicate a high prevalence of diabetes,undiagnosed diabetes or pre diabetic states -impaired glucose tolerance (IGT) or impaired

fasting glucose in coronary heart disease(CHD)

1. Bolk J, van der Ploeg T, Cornel JH, Arnold AE, Sepers J, Umans VA.Impaired glucose metabolism predicts mortality after a myocardialinfarction. Int J Cardiol 2001;79:207214.

2. Wascher TC, Sourij H, Roth M, Dittrich P. Prevalence of pathologicalglucose metabolism in patients undergoing elective coronary angiography.Atherosclerosis 2004;176:419421.


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` CHD is the number 1 cause of deathworldwide with diabetes increasing by 2-3

times the risk of CHD

Mathers C et al. The Global Burden of Disease in 2002: Data

Sources, Methods and Results, Geneva: World Health Organization;

2003


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1. Review the evidence linking hyperglycaemia in

patients with acute coronary syndrome (ACS)

with an adverse prognosis

2. Review strategies adopted so far to controlhyperglycaemia in acute cardiac care setting

3. Hypothesize a role for recently developed

drugs incretin analogues and mimetics


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` Hyperglycaemia is an acute stress response3

associated with less favourable outcome inpatient with or without known diabetes4

3.Bartnik M, Malmberg K, Norhammar A, Tenerz A, Ohrvik J, Ryden L. Newlydetected abnormal glucose tolerance: an important predictor of long-termoutcome after myocardial infarction. Eur Heart J 2004;25:19901997.

4.Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and

increased risk of death after myocardial infarction in patients with and withoutdiabetes: a systematic overview. Lancet 2000;355:773778.


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` GAMI (Glucose Tolerance in Patients withAcute Myocardial Infarction) trial

aim at assessing the prevalence of abnormalglucose regulation using oral glucose

tolerance test (OGTT) in patient withoutknown diabetes admitted for ACS

Bartnik M, Malmberg K, Norhammar A, Tenerz A, Ohrvik J, Ryden L. Newly detectedabnormal glucose tolerance: an important predictor of long-term outcome after myocardialinfarction. Eur Heart J 2004;25:19901997.


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Table 1: Glucose metabolism after discharge from a coronary care unit

and after 3 months in patients with AMI

BLOOD

GLUCOSE

AFTER OGTT

NORMOGLYCAEMI

A

11.1mmol/L

After hospital

discharge

(n=164)

34% (n=55) 35% (n=58) 31% (n=51)

Three months

after discharge

(n=144)

35% (n=50) 40% (n=58) 25% (n=36)


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Points :

- Hyperglycaemia after an ACS is not a

mere stress response

- The existence of a pancreatic beta cell

dysfunction and insulin resistance before

the ischaemic event seems more probable


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` Follow up of GAMI population indicatedthat there is substantially increased risk of

for further CHD events in patients with noknown diabetes with abnormal glucose

metabolism

Cakmak M et al. The value of admission glycosylated haemoglobin

level in patient with acute myocardial infarction. Canadian Journal ofCardiology2008; 24: 375-378


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1. GIK regime (glucose, insulin infusion and

potassium)

` OASIS-6 GIK5 and CREATE-ECLA6 trial :GIK infusion has no effects on mortality,

cardiac arrest or cardiogenic shock inACS

5. Diaz R et al. Glucose-insulin-potassium therapy in patients with ST-segmentelevation myocardial infarction. JAMA 2007; 298: 2399-2405

6. Mehta SR et al. Effect of glucose-insulin-potassium infusion on mortality in patientswith acute ST-segment elevation myocardial infarction:the CREATE-ECLArandomized controlled trial. JAMA 2005;293:437446.


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Problems with GIK :

` Harmful in the early phase of ACS due to

hyperkalaemia and fluid challenge

` Mean glucose level increased during

therapy (CREATEECLA) baseline

glucose level 9mmol/L to 10.4mmol/L after6 hours of GIK


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2. DIGAMI 1 trial (Diabetes mellitus, Insulin-

Glucose Infusion in AMI)

` Insulin-glucose infusion for 24hours afterhospital admission, followed by intensiveinsulin therapy after discharge was superiorto conventional treatment in improving acuteand long term glycaemic control

Malmberg KA, Efendic S, Ryden LE.F

easibility of insulin-glucose infusion indiabetic patients with acute myocardial infarction. A report from the multi center trial:DIGAMI. Diabetic Care 1994; 17: 1007-1014


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` 1 year mortality

18.6% in the infusion group vs 26.1% in

control group

` Long term mortality (3-4 years)

11% reduction

` Main benefit was seen during early postinfarction period no reinfarction and

reduced rate of heart failure


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3. DIGAMI 2 trial larger trial

i. Insulin infusion (24h) and then

subcutaneous insulin

ii. Insulin infusion (24h) and then standard

long term therapy

iii. Conventional therapy


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Limitation of DIGAMI 2 trial

` Premature stop slow recruitment rate

` Statistical power drop to below 50%

` Interpretation is uncertain


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DIGAMI 1 vs DIGAMI 2

` 1-year mortality 12.1%, but did not differbetween groups

` Gylcaemic control was better during insulin

infusion but no difference between groups andreduction in HbA1c could not be achieved

` Glucose level at admission was a strong and

independent predictor of long term mortality


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SYMPHONY studies

` Glucose lowering therapy associated with 90-day death, ACS and severe recurrentischaemia

i. Only insulin and/or sulfonylureas - 12%

ii. Biguanide only and/or thiazolidinedione

5%McGuire DK et al. Association of diabetes mellitus and glycemic control strategieswith clinical outcomes after acute coronary syndromes. Am Heart J 2004;147:246252.


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MINAP Myocardial Infarction National Audit

Project

` Conducted in 201 hospitals in England andWales

` Determined the effect of insulin in themanagement of hyperglycaemia in non-diabetic patients presenting with ACS

Weston C, Walker L, Birkhead J. Early impact of insulin treatment on mortality for

hyperglycaemic patients without known diabetes who present with an acute coronarysyndrome. Heart 2007;93:15421546.


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INSULIN WITHOUT

INSULIN

MORTALITY

7 days

30 days

11.6%

15.8%

16.5%

22.1%

RELATIVE

RISK OF

DEATH

7 days

30 days

56%

51%


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CARDINAL trial database

` Non-diabetic patients higher baselineglucose predicted higher mortality, and

greater 24h change in glucose predictedlower mortality at 30 days

Goyal A et al. Prognostic significance of the change in glucose level in thefirst 24 h after acute myocardial infarction: results from the CARDINALstudy. Eur Heart J 2006;27:12891297.


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` The European Society of Cardiology(ESC)/European Association for the Studyof Diabetes (EASD) recommends bloodglucose control by intensive insulin

treatment after heart surgery and inpatient with AMI

Ryden L et al. Guidelines on diabetes, pre-diabetes, and cardiovasculardiseases: executive summary. The Task Force on Diabetes andCardiovascular Diseases of the European Society of Cardiology (ESC) andof the European Association for the Study of Diabetes (EASD). Eur Heart J2007;28:88136.


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` 2008 ESC guidelines on ST-elevation MI

i. target glucose level 5-7.8mmol/L andavoiding blood glucose (BG) level 10mmol/Lregardless of prior diabetes history

iii. Non-ICU setting maintaining BG


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1. Glucagon-like-peptide 1 (GLP1)

` Incretin hormone contributes to glucose

regulation

` Reduces hyperglycaemia but does not

induce hypoglycaemia

` GLP1 analogue such as exenatide


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2.Inhibitors of DPP-4 (dipeptidyl peptidase-4)Incretin enhancers/gliptins such assitagliptin

` Prevent breakdown of endogenous GLP1

` Less nausea, less effect of hypoglycaemia


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GLP1 in ACS?

` Improves myocardial glucose uptake

` Improves left ventricular systolic function

` Reduces ischaemia/reperfusion injury in

experimental models


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` Diabetic patients with heart failure left

ventricular function improved after 5 weeks oftreatment

` Administration of GLP1 for 72 hours with anST elevation AMI and left ventricular

dysfunction after successful reperfusion

improved LVEF from 29 % to 39%

Sokos GG. Glucagon-like peptide-1 infusion improves left ventricular

ejection fraction and functional status in patients with chronic heart failure. J

Card Fail 2006;12:694699.


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`

Current evidence on the prognostic role ofhyperglycaemia in ACS allows direct

involvement in short term complications

` Hyperglycaemia on admission is important

prognostic factor in ACS


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` Patients with ACS and hyperglycaemia

receiving intensive insulin therapy have a

better outcome

` Insulin have a role in restoring cardiac andmetabolic dysfunctions common in

hyperglycaemia patients.


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`

The disturbances of glucose metabolism arewidely prevalent in ACS and related to an

adverse outcome, irrespective of the

presence or absence of previously diagnosed

diabetes

` GLP1 and its derivatives, also inhibitors of

DPP-4 are promising agents for glucose

lowering without hypoglycaemia to be tested

in the near future

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