coronary artery disease in diabetes
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Coronary Artery Disease in Diabetes
Lawrence A Leiter MD FRCPC FACPSt Michael’s HospitalUniversity of Toronto
Balkau B, et al. Lancet 1997; 350:1680.
0
5
10
15
20
25
30
35
Control
Diabetes
Ratio 2.5 Ratio 2.2 Ratio 2.1
WhitehallStudy
Mo
rtal
ity
rate
(dea
ths
per
1,0
00 p
atie
nt
year
s)
Paris ProspectiveStudy
Helsinki Policemen Study
Mortality Rate in DM vs Non DM
Haffner et al. NEJM 1998;339:229-34.
05
101520253035404550
No prior MI Prior MI
Non-DM
Type 2 DM
Is Diabetes a Coronary Equivalent?
Fatal & nonfatal MI in Subjects with and without Type 2 DM
7-year incidence of fatal and nonfatal MI in 1373 nondiabetic and 1059 diabetic subjects (p<0.001)
Inci
dence
(%
)
Non DMNon DMDMDM
*Defined in 1971-1975, followed up through 1982-1984.**Defined in 1982-1984, followed up through 1992-1993..
Trends in Mortality Rates for Ischemic Heart Disease in NHANES: DM vs Non DM
17.0
6.8
-16.6%-16.6% +10.7%+10.7%
Men, cohort 1*Men, cohort 1*
Men, cohort 2**Men, cohort 2**
Women, cohort Women, cohort 1*1*
Women, cohort Women, cohort 2**2**
-43.8%% -20.4%
14.2
7.6 7.4
4.22.4 1.9
(P=0.46) (P=0.76) (P<0.001) (P=0.12)
Ra
te p
er
100
0 p
ers
on
-ye
ars
0
5
10
15
20
Cohort 1Cohort 1Cohort 2Cohort 2
MenMen MenMenWomenWomen WomenWomen
Gu K et al. JAMA 1999;281:1291-1297
Glucose & CV Events: Meta-Regression
RR RR
NB: 2 h G=7.8: RR=1.58 (1.19-2.10) Fasting G=6.1: RR=1.33 (1.06-1.67)
After remove any DM: P = 0.0006 for 2 h GP = 0.06 for FPG
Coutinho M, Gerstein HC et al. Diabetes Care. 1999;22:233-240.
2 h Glucose Fasting Glucose
Glucose Levels and Risk for CVD
DM Cutpoint
CVD MicrovascularRR
1.0
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Causes of Death in DiabetesCauses of Death in Diabetes
46%
15%
11%
8%
20%
CV
CVA
Sepsis
Cancer
Other
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.
Enhancing the effectiveness of health carefor Ontarians through research
Prevalence of DM in Ontario
31%
0
1
2
3
4
5
6
7
1995 1996 1997 1998 1999
% D
M
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Life ExpectancyY
ears
0
10
20
30
40
50
60
70
80
90
100
Men Women
DMNo DM
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Risk of AMI - DM vs. Non-DM
Enhancing the effectiveness of health carefor Ontarians through research
Risk of AMI - DM vs. non-DM
AgeGroup
Women
OR 95% CI
Men
OR 95% CI
20-34 32.73 13.67-78.38 9.32 4.53-19.20
35-49 10.90 8.44-14.07 5.81 5.11-6.59
50-64 6.81 6.07-7.65 3.03 2.83-3.25
65-74 4.20 3.84-4.59 2.45 2.29-2.63
75 + 2.57 2.40-2.76 1.99 1.85-2.14
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0
200
400
600
800
1000
1200
1400
1600
1800
1995 1996 1997 1998 1999
Fiscal Year
AM
I ra
te p
er 1
00,0
00
Men - DM
Men - No DM
Women - DM
Women - No DM
Admissions for Acute Myocardial Infarction
9%
N=104,471 (30% DM)
DM vs. Non DM: Adjusted Reduction in Mortality 1994-2002
p<0.001 44.5 Women with diabetes
p<0.001 30.2 Men with diabetes
p<0.001 34.2 Women
p<0.001 23.5 Men
p Adjusted mortality decline (%)
Group
McGuire D. American College of Cardiology 2004 Scientific Sessions; Mar 2004; New Orleans
National Registry of Myocardial InfarctionN= 1,428,596 25% 0f U.S. acute care hospitals
Putative Mechanism for Increased Putative Mechanism for Increased Atherosclerosis in Type 2 DiabetesAtherosclerosis in Type 2 Diabetes
BLACK BOX Dyslipidemia
Hypertension
Hyperinsulinemia/insulin resistance
Hemostatic abnormalities
Hyperglycemia
AGE proteins
Oxidative stress
Endothelial Dysfunction
InflammationAdapted from Bierman EL. Arterioscler Thromb 1992;12:647-656.
Importance of CV Risk Factors in Diabetes
Eastman RC et al, Lancet, 1997;350(Supl 1):29-32
0
2
4
6
8
10
12
Odds Ratio
OR - CV Death
Microalbuminuria
Smoking
Diastolic BP
Cholesterol
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
Myocardial Infarction in Diabetic Patients
Prevalence of Diabetes 21%
Malmberg & Rydén, Eur Heart J 9:259, 1988
Fatal
NoYes
n = 341
Diabetes
Hospital
Fatal
One-year Reinfarction one-yearMortality
60
50
40
30
20
10
0
ACS and Diabetes Clinical Outcomes Up to 1 Year
% o
f p
atie
nts
1.83.9
7.1
8.9 7.9
14.4 14.1
21.3
P<0.0001
P=0.035
P<0.0001
P<0.0001
0
5
10
15
20
25
In-Hospital
Mortality
Non-fatal MI 1-y All-Cause
Mortality
1-y
Mortality/MI
N = 3429
N = 1149
No Diabetes
Diabetes
Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.
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
Causes of Adverse Outcome in Diabetic Patients with Acute Coronary Syndromes
Pump Failure Vulnerable non-infarcted myocardium– Metabolism– Vascular
Re-infarction
Greater Comorbidity
Glucose FFAPrior silent MIMore 3VD, distal diseaseSmaller arteriesImpaired reperfusion
More vulnerable plaquesGreater thrombogenicity
Renal impairmentHypertensionCVD, PVD
Glucose Intolerance in Chronic CAD
Fasting glucose in 1612 pts undergoing PCI 61% had Glucose Intolerance
– Known DM 24%
– Undx’ed DM (FG > 7.0) 18%
– IFG (Glucose 6.1 – 6.9 mmol/L) 18%
Muhlestein, et al. Am Ht J 2003;146:351.
Mortality by Fasting Glucose (Average 2.8 yrs)
Normal (< 6.0 mmol/L) 1.9%
IFG 6.6% p=0.002
Undiagnosed DM 9.5% p<0.001
DM 11.2% p<0.001
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Use of Cardio-protective DrugsUse of Cardio-protective Drugs• Ontario Drug Benefit Program - 65 yrs and over
?
?
??
%
0
10
2030
40
50
60
7080
90
100
BP 2+ BP ACEi Lipid
1994
1999
Target?
0
1
2
3
4
5
6
7
Male (N = 2334)
Female (N = 2809)
Risk for the Development of CHF –Risk for the Development of CHF –Framingham StudyFramingham Study
Ha
zard
Ra
tio
HTN MI Angina Diabetes LVH ValvularHeart Disease
Levy, D, et al. JAMA. 1996; 275: 1557-62.
Risk Factor
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
Across The Range of Glucose Tolerance, Women Have Greater LV Mass and More
Diastolic Dysfunction Than Men
Impact of Insulin Resistance on Myocardial Impact of Insulin Resistance on Myocardial Metabolism: Importance of FF Acid GenerationMetabolism: Importance of FF Acid Generation
Adapted from Oliver MF, Opie LH, Lancet 1994; 343: 155Adapted from Oliver MF, Opie LH, Lancet 1994; 343: 155
CV StressCV Stress
Catechols, CortisolCatechols, Cortisol
LipolysisLipolysis
Plasma FFAPlasma FFA
GlucoseGlucose
InsulinInsulin
CoronaryCoronaryOcclusionOcclusion
LysophospholipidsLysophospholipids
CaCa2+2+ overload overload Enzyme lossEnzyme loss
GlycolysisGlycolysis Glucose Oxidation Glucose Oxidation
MembraneMembraneDamageDamage
ArrhythmiasArrhythmias
PhospholipidsPhospholipids
TGTG
FFAFFA
Acyl CoAAcyl CoAAcylcarnitineAcylcarnitine
00
0.1
0.2
0.3
0.4
0.5
0.6
0.7
11
DIGAMI: Benefit of Tight Glycemic Control in AMI:DIGAMI: Benefit of Tight Glycemic Control in AMI:Major Benefit in “No Insulin - Low Risk” CohortMajor Benefit in “No Insulin - Low Risk” Cohort
Malmberg, K et al BMJ 1997; 314: 1512-1515Malmberg, K et al BMJ 1997; 314: 1512-1515
Insulin-glucoseInsulin-glucoseInfusionInfusion
ControlControl
MortalityMortality
Years in StudyYears in Study
n = 314n = 314
n = 306n = 306
00 22 33 44 55
p = .0111p = .0111
00
0.1
0.2
0.3
0.4
0.5
0.6
0.7
11
Insulin-glucoseInsulin-glucoseInfusionInfusion
ControlControl
MortalityMortality
Years in StudyYears in Study
n = 133n = 133
n = 139n = 139
00 22 33 44 55
p = .004p = .004
Total CohortTotal Cohort No Insulin - Low RiskNo Insulin - Low Risk
19% @ 1 year
26%
CHF accounted for 66% of all deaths
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
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
Mathew V et al Circulation 2004;109:10
Adjusted Relative Risk
DM worse
Death MI TVR
0 1 2 3
Death
MI
TVR
Comp
Reduced Target Vessel Restenosis (TVR) after PCI Outcomes in Diabetes with TAXUS Coated Stents
TAXUS IV Stone et al, Late Breaking Clinical Trials ACC, 2003
02468
101214161820
No Diabetes Diabetes Oral
Meds
Diabetes Insulin
TV
R (
%)
Control TAXUS
Reasons for Increased Vascular Risk in DM
Accelerated Atherosclerosis
Underutilization of Evidence Based
Therapies
Altered Cardiac Metabolism
Unrecognized DM
Increased Restenosis Post PCI
0
10
20
30
40
50
60
Diabetes Confers a Doubling of Risk for Early MI Diabetes Confers a Doubling of Risk for Early MI Mortality Despite Advances in Cardiac CareMortality Despite Advances in Cardiac Care
Early MortalityEarly Mortalityfrom Acute MIfrom Acute MI
Pre-CCU EraPre-CCU Era(pre-1962)(pre-1962)
CCU EraCCU Era(1962-1984)(1962-1984)
Lytic EraLytic Era(1984-2000)(1984-2000)
DiabetesDiabetes
Total GroupTotal Group
Defibrillation Defibrillation Hemodynamic Hemodynamic
MonitoringMonitoring
Thrombolysis Thrombolysis Beta-blockade Beta-blockade
AspirinAspirin
PCI EraPCI Era(2000-- )(2000-- )
PCIPCIIIbIIIa InhibitorsIIbIIIa Inhibitors
ClopidrogelClopidrogelStatinsStatins
DigoxinDigoxinDiureticsDiuretics
From Richard NestoFrom Richard Nesto
CDA Guidelines - Cardiorenal Prioritization
In all PatientsIn all Patients1.1. ACE inhibitorACE inhibitor2.2. ASAASA3.3. Lipid Control Lipid Control
(statin) (statin) 4.4. BP ControlBP Control5.5. Also as required:Also as required:
– Glycemic controlGlycemic control– LifestyleLifestyle– Smoking cessationSmoking cessation
3. Control of Nephropathy
2. Hypertension Control
1. Vascular Protection
Risk of CAD in DM
• 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
Conclusions: