Coronary Artery Disease in Diabetes

1
Coronary Artery Disease in Diabetes

• Lawrence A Leiter MD FRCPC FACP
• St Michaels Hospital
• University of Toronto

2
Mortality Rate in DM vs Non DM
Ratio 2.5
Ratio 2.2
Ratio 2.1
Control
Mortality rate(deaths per 1,000 patient years)
Diabetes
Whitehall Study
Helsinki Policemen Study
Paris ProspectiveStudy
Balkau B, et al. Lancet 1997 3501680.
3
Is Diabetes a Coronary Equivalent?

• Fatal nonfatal MI in Subjects with and without
  Type 2 DM

50
45
40
35
30
Incidence ()
25
20
15
10
5
0
No prior MI
Prior MI
7-year incidence of fatal and nonfatal MI in 1373
nondiabetic and 1059 diabetic subjects (plt0.001)
Haffner et al. NEJM 1998339229-34.
4
Trends in Mortality Rates for Ischemic Heart
Disease in NHANES DM vs Non DM
Non DM
20
Men
Men
Women
Women
17.0
Men, cohort 1 Men, cohort 2 Women, cohort
1 Women, cohort 2
14.2
15
Cohort 1 Cohort 2
Rate per 1000 person-years
10
7.6
7.4
6.8
4.2
5
2.4
1.9
0
-16.6
10.7
-43.8
-20.4
(P0.46)
(P0.76)
(Plt0.001)
(P0.12)
Defined in 1971-1975, followed up through
1982-1984.Defined in 1982-1984, followed up
through 1992-1993. .
Gu K et al. JAMA 19992811291-1297
5
Glucose CV Events Meta-Regression
Fasting Glucose
2 h Glucose
RR
RR
NB 2 h G7.8 RR1.58 (1.19-2.10) Fasting
G6.1 RR1.33 (1.06-1.67)
After remove any DM P 0.0006 for 2 h G P
0.06 for FPG
Coutinho M, Gerstein HC et al. Diabetes Care.
199922233-240.
6
Glucose Levels and Risk for CVD
Microvascular
CVD
RR
1.0
DM Cutpoint
7
Causes of Death in Diabetes
20
46
8
11
15
Cancer
CV
Other
CVA
Sepsis
Hux JE, et al. Diabetes in Ontario, an ICES
Practice Atlas 2003.
8
Prevalence of DM in Ontario
7
31 ?
6
5
4
DM
3
2
1
0
1995
1996
1997
1998
1999
9
Life Expectancy
100
90
80
70
60
DM
Years
50
No DM
40
30
20
10
0
Men
Women
10
Risk of AMI - DM vs. Non-DM
11
Risk of AMI - DM vs. non-DM
12
Admissions for Acute Myocardial Infarction
9 ?
N104,471 (30 DM)
13
DM vs. Non DM Adjusted Reduction in Mortality
1994-2002
National Registry of Myocardial Infarction N
1,428,596 25 0f U.S. acute care hospitals
McGuire D. American College of Cardiology 2004
Scientific Sessions Mar 2004 New Orleans
14
Putative Mechanism for Increased Atherosclerosis
in Type 2 Diabetes
BLACK BOX

• Dyslipidemia
• Hypertension
• Hyperinsulinemia/insulin resistance
• Hemostatic abnormalities
• Hyperglycemia
• AGE proteins
• Oxidative stress
• Endothelial Dysfunction
• Inflammation

Adapted from Bierman EL. Arterioscler Thromb
199212647-656.
15
Importance of CV Risk Factors in Diabetes
Eastman RC et al, Lancet, 1997350(Supl 1)29-32
16
Acute Coronary Syndromes in the Diabetic Patient

• Greater propensity for plaque rupture
• Worse outcome
• Increased coagulation
• Greater extent / severity of CAD
• More pump failure
• Worse outcome of revascularisation

17
Myocardial Infarction in Diabetic
Patients Prevalence of Diabetes 21
Diabetes
60 50 40 30 20 10 0
No
Yes
n 341
Fatal
Fatal
Hospital
One-year
Reinfarction one-year
Mortality
Malmberg Rydén, Eur Heart J 9259, 1988
18
Oasis Study Total Mortality
Diabetes/CVD , (n 1148)
0.25
Diabetes/CVD -, (n 569)
No Diabetes/CVD , (n 3503)
RR 2.88 (2.37-3.49)
No Diabetes/CVD -, (n 2796)
0.20
RR1.99 (1.52-2.60)
0.15
Event rate
0.10
RR1.71 (1.44-2.04)
0.05
RR1.00
0.0
3 6 9 12 15 18
21 24
Months
Malmberg K et al. Circulation 200010210141019.
19
FRISC II Diabetes Not CAD Extent is the Most
Important Independent Predictor of Death and MI
RR
95 CI
p
Age
0.98
(0.74-1.32)
NS
Gender
0.80
(0.64-0.99)
0.039
Hypertension
1.31
(0.86-2.00)
0.21
Diabetes
2.40
(1.47-3.91)
0.001
Smoking
0.96
(0.75-1.22)
0.73
Previous Angina
1.22
(0.87-1.72)
0.25
Previous MI
1.85
(1.17-2.93)
0.008
ST-depression
1.22
(0.80-1.86)
0.348
1.66
(1.03-2.68)
0.038
Troponin T gt0.03 mg/l
3-VD/LMD
1.06
(0.84-1.33)
0.62
0.5
1
4
Norhammer A et al. JACC 2004 43 585-91
20
ACS and Diabetes Clinical Outcomes Up to 1 Year
25
Plt0.0001
No Diabetes
20
21.3
N 3429
Plt0.0001
Diabetes
15
N 1149
of patients
14.4
14.1
P0.035
10
8.9
7.9
Plt0.0001
7.1
5
3.9
1.8
0
In-Hospital
Non-fatal MI
1-y All-Cause
1-y
Mortality
Mortality
Mortality/MI
Yan R, et al. Can J Cardiol 200319(suppl
A)260A.
21
Why are Diabetic Patients at Increased Risk after
ACS ? (1)

• Older
• More female
• Atypical symptoms
• Dyspnoea
• Nausea
• Fatigue
• Vomiting
• Disturbance of glycemic control
• Delayed presentation
• Less use of proven treatment

22
Causes of Adverse Outcome in Diabetic Patients
with Acute Coronary Syndromes

• Pump Failure
• Vulnerable non-infarcted myocardium
• Metabolism
• Vascular
• Re-infarction
• Greater Comorbidity

More vulnerable plaques Greater thrombogenicity
Renal impairment Hypertension CVD, PVD
23
Admission Plasma Glucose / Impaired GT
Independent Risk Factors for Prognosis after AMI

• 181 AMI with admission glucose lt 11.1
• OGT prior to d/c and at 3 mo.
• Mean admission glucose 6.5 mm/L
• Impaired glucose tolerance or undiagnosed
  diabetes
• D/C 3 mo
• IGT 35 40
• New DM 31 25

Norhammar et al Lancet 20023592140
24
Glucose Intolerance in Chronic CAD

• Fasting glucose in 1612 pts undergoing PCI
• 61 had Glucose Intolerance
• Known DM
  24
• Undxed DM (FG gt 7.0) 18
• IFG (Glucose 6.1 6.9 mmol/L) 18

• Mortality by Fasting Glucose (Average 2.8 yrs)
• Normal (lt 6.0 mmol/L) 1.9
• IFG
  6.6 p0.002
• Undiagnosed DM 9.5 plt0.001
• DM 11.2 plt0.001

Muhlestein, et al. Am Ht J 2003146351.
25
Use of Cardio-protective Drugs

• Ontario Drug Benefit Program - 65 yrs and over

?
?
?
?

26
CHRC Vascular Protection (VP) Registry
3,422 / 5000 patients 186 MDs enrolling December
9, 2001 December 9, 2003

Newfoundland 10 MDs n107
New Brunswick 10 MDs n144
British Columbia26 MDs n555
Saskatchewan 16 MDs n242
Quebec 34 MDs n508
P.E.I
Manitoba13 MDs n496
Alberta7 MDs n61
Ontario 62 MDs N1136
Nova Scotia8 MDs n173
5000 patients with either/or CAD,PAD,CVD,
Diabetic patients with at least one CAD risk
factor
Data on file at Canadian Heart Research Centre
27
CHRC Vascular Protection Registry DM vs Non DM
Diabetes n1,871 (55.8) 65 (55,72) 38 132
(122,144) 78 (70,80) 104 (95,113) 31
(27,35) 37 22 18 13 10
No Diabetes n1,482 (44.2) 68 (60,76) 31 130
(120,140) 76 (70,80) 98 (90,106) 28
(25,31) 82 49 43 20 13
Age, years Female () Systolic BP mm
Hg Diastolic BP mm Hg Waist circumference
(cm) Body Mass Index (kg/m2) Coronary artery
disease () Prior MI () Prior PCI or CABG
() Cerebrovascular disease () Peripheral
vascular disease ()
Median (25th, 75th percentiles)
All comparisons p?0.004
Data on file at Canadian Heart Research Centre
28
CHRC Vascular Protection Registry DM vs Non DM
Antiplatelets
Statins
ACE Inhibitors
of Patients
of Patients
of Patients
100
plt0.001
plt0.01
plt0.01
plt0.01
plt0.01
plt0.01
plt0.001
plt0.01
89.5
86.3
86
80
82.8
80.1
79.6
79.3
77.2
74.9
71.9
70.2
71.2
68.3
67.9
65.9
62.1
60
61.9
60.6
40
20
0
Baseline
6 Months
1 Year
Baseline
6 Months
1 Year
Baseline
6 Months
1 Year
Diabetes
No diabetes
Data on file at Canadian Heart Research Centre
29
ACS and Diabetes Early In-hospital Management
P lt 0.001
100
Plt0.05
90
94.5
Non-DM
91.4
90.9
89.3
80
N 3429
P lt 0.001
70
DM
60
62.8
N 1149
50
of patientS
50.3
40
30
20
P lt 0.005
10
7.6
5.2
0
Reperfusion Antiplatelet Heparin
GpIIb/IIIa inhibitor
30
ACS and Diabetes In-hospital Cath / Revasc
P 0.006
41.0
36.4
N 3429
P lt 0.001
of Patient
18.0
12.7
N 1149
4.0
3.8
31
ACS and Diabetes Medication Use at Discharge
100
P0.008
90
P0.10
90.3
87.5
80
Plt0.0001
76
70
73.6
65.6
60
Non-DM
50
53.9
54.5
52.1
of patients
N 3429
Plt0.0001
40
36.3
30
DM
25.2
20
N 1149
10
0
Anti-platelet Beta ACE-I Ca
Channel Lipid Blocker
Blocker lowering
32
Risk for the Development of CHF Framingham Study
Hazard Ratio
HTN
MI
Angina
Diabetes
LVH
Valvular Heart Disease
Risk Factor
Levy, D, et al. JAMA. 1996 275 1557-62.
33
Congestive Heart Failure Is More Common in
Patients With Type 2 Diabetes
lt45
lt45
95
95
Age at Baseline
CHF present in 14 DM subjects at inception with
8 new cases over 5 years
Nichols, GA, et al. Diabetes Care. 2001 24
1614-9
34
Impact of Diabetes on Risk for New CHF Following
Acute Coronary Syndromes OASIS
Diabetes() and CVD()
Event Rate and RR forLong-term Outcomes
No Diabetes and CVD()
Event Rate
Diabetes() and CVD(-)
.30
No Diabetes and CVD(-)
Crude EventRate
RR 3.43 (2.85-4.13)
.25
NoDM
Adjusted RR(95 CI)
Parameter
DM
P
.20
RR 2.19 (1.86-2.58)
Total mortality 18 10 1.57 lt0.001 CVD
death 14 8 1.49 lt0.001 New MI 12 9 1.34 lt0.001 Str
oke 5 3 1.45 0.009 New CHF 21 12 1.41 lt0.001
.15
RR 1.98 (1.52-2.57)
.10
.05
RR 1.00
0
3
12
18
24
6
9
15
21
0
Months
Malmberg K et al. Circulation. 20001021014-1019
35
Across The Range of Glucose Tolerance, Women Have
Greater LV Mass and More Diastolic Dysfunction
Than Men
Left Ventricular Mass Increases With
Deteriorating Glucose Tolerance, Especially in
Women Independence of Increased Arterial
Stiffness or Decreased Flow-Mediated Dilation
The Hoorn Study
Diabetes Care 2004 27
522-529

Impact of Glucose Intolerance and Insulin
Resistance on Cardiac Structure and Function
Sex-Related Differences in Framingham Study

Circulation 2003 107 448-454
36
Impact of Diabetes on Cardiac Structure and
Function in Women Strong Heart Study
mean SD
Devereux, RB et al, Circ 2000 101 2271-2276
37
Hospitalization for Heart Failure in the Presence
of a Normal Left Ventricular Ejection
Fraction J Am Coll Cardiol 2004 43
1432-1438

• Prospective identification of patients admitted
  with pure CHF and EFgt50 in NY Heart Failure
  Registry
• 619 patients
• 73 women
• Women 8 years younger than men
• Co-morbid conditions
• -Hypertension 78
• -Diabetes 46
• -Obesity 46
• -CAD 40
• -Increased LV Mass

Diabetes and/or insulin resistance syndromes
underlie most cases of non-systolic CHF,
particularly in women
38
Impact of Insulin Resistance on Myocardial
Metabolism Importance of FF Acid Generation
CV Stress
CoronaryOcclusion
Catechols, Cortisol
Lipolysis
Insulin
TG FFA Acyl CoAAcylcarnitine
Phospholipids
Plasma FFA
Glucose
Lysophospholipids
Membrane Damage
Glycolysis Glucose Oxidation
Ca2 overload
Enzyme loss
Arrhythmias
Adapted from Oliver MF, Opie LH, Lancet 1994
343 155
39
DIGAMI Benefit of Tight Glycemic Control in
AMIMajor Benefit in No Insulin - Low Risk
Cohort
Mortality
Mortality
Total Cohort
No Insulin - Low Risk
0.7
0.7
p .0111
p .004
Control
Control
0.6
0.6
Insulin-glucoseInfusion
Insulin-glucoseInfusion
n 314
0.5
0.5
n 133
0.4
0.4
26
n 306
0.3
0.3
0.2
0.2
n 139
19 _at_ 1 year
0.1
0.1
0
0
1
0
2
3
4
5
1
0
2
3
4
5
Years in Study
Years in Study
CHF accounted for 66 of all deaths
Malmberg, K et al BMJ 1997 314 1512-1515
40
Coronary Revascularisation in DM

• No increase in CABG operative mortality
• Greater peri-op morbidity wound, renal failure
• Worse long term out-look after CABG
• PCI More re-stenosis over first 6/12
• PCI Complete revascularisation often not
  achieved

41
DM Mortality Rates in RCTs Comparing CABG vs.
Coronary Angioplasty
Koon-Hou Mak et al. European Heart Journal 2003
24 1087-1103
42
DM still has Worse Prognosis Post PCI in Modern
Era

• PRESTO Study
• 11,482 patients
• 43 diabetic
• Tested tranilast to prevent restenosis
• Compared out-come in DM vs Non-DM
• 9 month follow-up

Adjusted Relative Risk
Death MI TVR
Comp
TVR
MI
Death
0
1
2
3
DM worse
Mathew V et al Circulation 200410910
43
Reduced Target Vessel Restenosis (TVR) after PCI
Outcomes in Diabetes with TAXUS Coated Stents
20
Control
TAXUS
18
16
14
12
10
TVR ()
8
6
4
2
0
No Diabetes
Diabetes Oral
Diabetes Insulin
Meds
TAXUS IV Stone et al, Late Breaking Clinical
Trials ACC, 2003
44
Reasons for Increased Vascular Risk in DM

• Accelerated Atherosclerosis
• Underutilization of Evidence Based
• Therapies
• Altered Cardiac Metabolism
• Unrecognized DM
• Increased Restenosis Post PCI

45
Diabetes Confers a Doubling of Risk for Early MI
Mortality Despite Advances in Cardiac Care
Early Mortalityfrom Acute MI
Diabetes
DigoxinDiuretics
Total Group
Defibrillation Hemodynamic Monitoring
Thrombolysis Beta-blockade Aspirin
PCIIIbIIIa InhibitorsClopidrogelStatins
Pre-CCU Era(pre-1962)
CCU Era(1962-1984)
Lytic Era(1984-2000)
PCI Era(2000-- )
From Richard Nesto
46
CDA Guidelines - Cardiorenal Prioritization

• In all Patients
• ACE inhibitor
• ASA
• Lipid Control (statin)
• BP Control
• Also as required
• Glycemic control
• Lifestyle
• Smoking cessation

1. Vascular Protection
2. Hypertension Control
3. Control of Nephropathy
47
Risk of CAD in DM
Conclusions

• Risk of CAD in persons with DM is increased but
  there is recent evidence suggesting that we are
  beginning to turn the tide
• Pathophysiology of accelerated atherosclerosis is
  multifactorial
• Undertreatment is responsible for some of the
  increased vascular risk in diabetes despite
  proven benefit of evidence based therapies in DM
• Antihyperglycemic treatments may also impact on
  CV outcomes in DM