acute coronary syndromes - european society of...

Lars RydénKarolinska InstitutetStockholm, Sweden

Management of diabetes in patients with

coronary artery disease

Acute coronary

syndromes

Changing fenotype

Hyperglycemia and acute coronary syndromes

OGTT

75 g glucose in 200 ml water

Capillary blood glucose

before and 120 min after

glucose ingestion

GAMI

Study design

Patientsn= 181 MI, no diabetes

B-glucose <11.1 mmol/L

Controls

n=185

OGTT at dischargen = 168

Abnormal 67%

DM

33%

NGT

33%

IGT

34%

GAMI

Results

(Norhammar et al. Lancet. 2002;359:2140)

NGT

65%

DM11%

IGT

24%

Controlsn = 185

(Bartnik et al J Intern Med. 2004; 256: 288)

Abnormal 35%

10

8

6

4

2

0

* ***

***

***

***Patients n=145

Controls n=185

Mm

ol or

pm

ol/L

Metabolic variables in the GAMI trialPatients with AMI without diabetes vs. age and sex matched controls

(Bartnik et al J Intern Med 2004; 256:288)

The MI patient now and thenSecular trends in the risk factor pattern

Risk factor 1963 2003

Smoking (%) 56

Regular phys act (%) 32

Stress 17 17

Body Mass Index 24.8

Waist circumference (cm) 87

S-Cholesterol (mmol/l) 6.4

S-Triglycerides (mmol/l) 1.3

Blood pressure (mmHg) 138/91

Diabetes (%) 3.6

50 year old men in Gothenburg

24

26.8

95

1.7

6.6

22

5.5

135/85

(Wilhelmsen et al. J Intern Med 2008;263:636)

The patient with myocardial infarction now and thenSecular trends in risk factor pattern

Lean, stressed,

chain-smoking CEO

Passed time

Sedenatary, overweight labourer

with the metabolic syndrome

Present time

Changing fenotype

Influence on prognosis


The Swedish CCU registry 1995-2006

Time trends in 1-year mortality in AMI-patients

with and without diabetes

(Norhammar et al Heart . 2007; 93:1577 )

(Norhammar et al data on file 2003-2006)

No

Yes

Diabetes

1995 1997 1999 2001 2003 2005 2007

Mo

rta

lity (

%)

S-Creatinine (40 mmol/L)

Previous CHF

Previous MI

Smoking

Gender (Male = 1)

Diabetes duration (one year)

Age (ten years)

Updated FBG (+3 mmol/L)

0.5 1 3

HR p

1.20 <0.001

2.14 <0.001

1.00 0.64

0.89 0.40

1.14 0.48

1.18 0.26

1.71 <0.001

1.13 <0.001

2

Log scale

Predictors of death in patients with diabetes

and myocardial infarction

(Malmberg et al. Eur Heart J 2005; 26:650)

From DIGAMI 2Independent risk predictors for mortality

(Norhammar et al Diabetes Care 1999, 22: 1827)

Admission glucose predicts mortality in MI patients

without known diabetes

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27 months

Event free survival (%)

2P = 0.0029 (Log-Rank test)

P-glucose median

7.4 mmol/l

P-glucose > median

7.4 mmol/l

(Sinnaeve et al. Arch Intern Med 2009;169: 402)

Global Registry of Acute Coronary Events n= 57 406

Admission glucose n=22.001 Fasting glucose n=13.526

Age (years) 65 67 68 66 66

Sex (female; %) 32 32 37 40 43

History of DM (%) 12 20 54 80 73

STEMI 35 43 44 42 39

NSTEMI 33 34 35 33 37

Unstable angina 32 24 22 25 25

F-glucose (mmol/l) 5.6 5.6-6.9 7-11 11-16.6 >16.7

Proportion (%) 41 32 21 5 1

Predictors of death in patients with

acute coronary syndromes

Glucose level (mmol/l)

5.6-6.9 Admission

Fasting

7.0-10.9 Admission

Fasting

11.0-16.4 Admission

Fasting

16.5 Admission

Fasting

1 2 3 4 5 6 7 8 9

Adjusted OR for in-hospital death

(Sinnaeve et al. Arch Intern Med 2009;169: 402)

40

20

00 3 6 9 12 15 18 21 24 27 months

2P= 0.0029 (Log-Rank test)

5.5 11.1 16.7

16

12

8

4

022

Pro

babili

tyof death

(%

)

Fasting Glucose (mmol/l)

Diabetes

All

No diabetes

Predictors of death in patients with

acute coronary syndromes

DAG*

PKC activation

TGF Basal membrane

thickening

cPLA2 Increased

PG’s membrane

Na+/K+ATP-ase permeability

VEGF PKC Cellular growth &

neovascularisation

ANP BNP

TGF Cardiomyopathy

PAI-1 Fibrinolysis

Vascular occlusion

Decreased

ET-1 blood flow &

() eNOS vascular reactivity

PDH inactivation

* = DAG = DiAcylGlycerol

Linking dysglycemia to cardiovascular disease

(Brownlee Nature 2001;414:813)

(Garcia Soriano et al Nature Medicine 2001;7:1)

Changing fenotype

Influence on prognosis

Benefits with glucose lowering therapy

In acute coronary syndromes

Cardiovascular long-term safety


Efficacy of different glucose lowering drugs

Biguanides

Sulfonylureas

Alpha-glucosidase inhibitors

Glitazones (TZDs)

Incretin enhancers/GLP-analogs

0.5 - 1.0

1.0 - 1.5

Insulin 1.0 - 2.0

1.0 – 1.3

1.0 - 1.5

1.0 - 1.5

Documented glucose lowering capacity

Drug Decrease in HbA1c (%)

Rationale for insulin administration in ACS patients

Potential

benefits with

insulin

in acute illness

Antihrombotic

TF PAI-1

Glucose

lowering

Vasodilation

Platelet inhibition

NO-release

eNOS cAMP

Antioxidant

ROS

Cardioprotective

Neuroprotective

Antiapoptocic

Antiinflammatory

NF-B MCP-1

ICAM 1 CRP

(After Dandona et al Rev Cardiovasc Med 2006; 7: S25)


Glucose-Insulin-Potassium for Acute Myocardial Infarction:

Continuing Controversy Over Cardioprotection

Robert A Kloner and Richard W Nesto

Circulation 2008; 117: 2523 – 2533


Metabolic modulationGlucose-Insulin-Potassium Infusion (GIK)

Metabolic controlGlucose lowering

Myocardial infarction

STEMI

n = 20 201

Infusion 24 hours

25 % glucose

Insulin 50 IU/L

80 mEq/L potassium

Rate 1.5 ml/kg/h

HR=1.03 (0.95-1.13) p=0.45

Metabolic modulation with GIK in myocardial infarction

The CREATE-ECLA study

(CREATE-ECLA investigators JAMA 2005;293:437)

Plasma Glucose

mmol/L

9.0 10.4 8.2 8.6 7.5

0

2

4

6

8

10

12

APG 6h 24h

Infusion

Control

Glucose-insulin-potassium in myocardial infarction

The CREATE-ECLA study

(CREATE-ECLA investigators JAMA 2005;293:437)

RR = 0.72 [0.92-0.55] p = 0.011

Absolute reduction 11%

Controls

Intensive

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 1 2 3 4 5

Year

Mortality

Mean follow-up 3.4 år (1.6-5.6)

(Malmberg for DIGAMI study group Brit Med J 1997, 314:1512)

Long-term mortality in DIGAMI 1

Reduction in HbA1c 1%

Glucose loweringPatients with myocardial infarction and type 2 diabetes

Group 1 (insulin+insulin)

Group 2 (insulin+conventional)

Group 3 (conventional)

(Malmberg et al Eur Heart J 2005;26:650)

Suspect MI + Type 2 diabetesor B-glucose >11 mmol/L

Long-term outcome in DIGAMI 2


Group 1 (insulin+insulin)

Group 2 (insulin+conventional)

Group 3 (conventional)

Number at risk474 367 299 254 202 154 87473 381 317 261 225 170 91306 241 214 175 145 119 80Group 3

Group 1Group 2

0

5

10

15

20

25

30

35

40

45

0.5 1.0 1.5 2.0 2.5 3.0 Years0

Group 1 vs Group 3

HR = 1.22 (0.95 - 1.56) p = 0.115

Event ra

te (

%)


Long-term outcome in DIGAMI 2


Group 1

Group 2

Group 3

mmol/L

Baseline 24 h 3 6 12 18 24 30 36 months0

2

4

6

8

10

12

14

16

18

20

No Group 1 469 454 329 313 295 228 197 144 114Group 2 469 452 331 320 304 219 195 151 108Group 3 304 282 214 199 184 154 125 98 77

*

DIGAMI 2Blood glucose over time by treatment group


1.93 (1.18-1.3.17)

1.48 (1.09-1.99)

≥6.6 mmol/L/ ≥120 mg/dl

(n=276; 107 deaths)

3.1-6.5 mmol/L/ 56-119 mg/dl

(n=364; 101 deaths)

≤3.0 mmol/L/ ≤55 mg/dl

(n=44; 20 deaths)

Reference

-3.5 -2.5 -1.5 -.5 .5 1.5 2.5 3.5

Hypoglycemia and acute coronary syndromes

(Svensson et al Eur Heart J 2005;26:1255)

Lowest blood glucose during hospitalisation for MI

713 patients with diabetes

Adjusted 2-year mortality

Symptomatic hypoglycemia during hospitalisation

in DIGAMI 2

(Mellbin et al. Heart 2009; 95:721)

0.50 0.70 1.00 1.45 2.00 4.00

Unadjusted

Unadjusted

Unadjusted

Unadjusted:Adjusted

UnadjustedAdjusted

UnadjustedAdjusted

0.50 0.70 1.00 1.45 2.00 4.00

Symptomatic hypoglycemia during hospitalisation

in DIGAMI 2

Adjusted for age, sex, smoking, diabetes duration, previous MI, CHF,

renal function, PCI and CABG and updated mean fasting glucose

Symptomatic hypoglycemia n=45

Cardiovascular mortality

(Mellbin et al. Heart 2009; 95:721)

Total mortality

Death/Stroke/Reinfarction

Hypoglycaemic events identifies patients at high

risk by other reasons

e.g. low body weight and long diabetes duration

Insulin and cardiovascular events in DIGAMI 2

(Mellbin et al. Europ Heart J 2008; 29:166)

Impact of various glucose lowering treatments on CV-events

Composite MI and stroke

Glucose lowering treatment in myocardial infarction

Impact of various

glucose lowering

treatments on

mortality, morbidity and

malignancies during

extended follow up

Median 4.1 years

(interquartile range = 2.6–5.4

max 8.3)

Insulin and cardiovascular events in DIGAMI 2

(Mellbin and Rydén Data on file )

Insulin and malignancies in DIGAMI 2

(Mellbin and Rydén Data on file )

(Deedwania et al. Circulation 2008;17:1610)

Glycemic control and acute coronary syndromesSummary of studies in patients with ACS and hyperglycemia

Hyperglycemia and Acute coronary Syndrome. A Scientific Statement

from the American Heart Association Diabetes Committee

of the Council on Nutrition, Physical Activity and Metabolism

P Deewania, Kosiborod M, Barret E, Ceriello A, Isley W, Mazzone T

and Raskin P

Circulation 2008; 17:1610

Study Glucose difference Outcome

(intensive vs. control)

DIGAMI I 9.6 vs 11.7 mmol/l (24-h) 1- year mortality 19 vs 26%

DIGAMI 2 No significant 2-year mortality no differenceTarget not reached intensive group

CREATE-ECLAHigher 24 h-glucose in GIK-group 30-day mortality no difference

(8.6 vs. 7.5 mmol/l)

”Control of hyperglycemia may be more critical

than the dose of insulin administered”

Glycemic control and acute coronary syndromesSummary of studies in patients with ACS and hyperglycemia

Metabolic support with high dose GIK has no role in the treatment of ST-elevation AMI

Hyperglycaemia is an important independent risk factor for future events following AMI

Diabetic patients should have an intensive glucose control after an AMI. Normalisation!?

Hypoglycaemic episodes during hospitalization do not influence long-term prognosis. Some patients more vulnerable

Agents used for long-term glucose control may play an important role for future morbidity and mortality

Thanks for the attention!!!

Management of diabetes in patients with

coronary artery disease

Acute coronary

syndromes

acute coronary syndromes - european society of...

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