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Clinical Evaluation and Nonlipid
Treatment of Coronary Artery
Disease in the Diabetic Patient
Richard Nesto, MD
Prevalence of Asymptomatic CAD in
Diabetes Mellitus
Positive
Positive
Koistinen MJ. BMJ 1990;301:92-95.
Type 2
Type 1
Controls
Naka M et al. Am Heart J 1992;123:46-53.
Type 2
Controls
MiSAD Group. Am J Cardiol 1997;79:134-139.
Type 2
Rutter MK et al. Am J Cardiol 1999;83:27-31.
Type 2 w microalb
Type 2 w/o microalb
Le A et al. Am J Kidney Dis 1994;24:65-71.
Type 1 Renal Transplant
Holley JL et al. Am J Med 1991;90:563-570.
Type 1 & 2 Renal Transplant
ETT
Angiography
n = 64
n = 72
n = 80
36%
24%
9%
9%
11%
9%
n = 142
n = 149
31%
30%
12.1%
5.3%
n = 925
12.1%
n = 43
n = 43
65%
40%
6.4% (thal201)
—
—
58%
35%
55%
43%
Indications for Cardiac Testing in
Diabetic Patients
 Typical or atypical cardiac symptoms
 Resting ECG suggestive of ischemia or infarction
 Peripheral or carotid occlusive arterial disease
 Sedentary lifestyle or plan to begin a vigorous exercise program
 Two or more of the risk factors listed below
- Total cholesterol >240 mg/dL, LDL cholesterol >160 mg/dL, or HDL
cholesterol <35 mg/dL
- Blood pressure >140/90 mmHg
- Smoking
- Family history of premature CAD
- Positive micro/macroalbuminuria
Factors Limiting Accuracy of Noninvasive
"Stress" Tests for CAD
 Hypertensive Cardiomyopathy
 Diabetic Cardiomyopathy
 Autonomic Cardiomyopathy
 Renal Insufficiency
 Microvascular Dysfunction
Benefits of Early Detection of CAD
 Implement more aggressive CHD prevention
regimen
 Initiate anti-ischemic medications
 Identify patients who would benefit from
revascularization
 Educate patients to recognize coronary
symptoms
MEN
180
No Glucose
Intolerance
160
140
174
Glucose
Intolerance
120
119
100
90
80
77
60
40
20
0
59
50
38
24
105
135
165
Age-adjusted CV Event Rate/1,000
Age-adjusted CV Event Rate/1,000
Blood Pressure and CVD: Framingham Heart Study
WOMEN
180
No Glucose
Intolerance
160
140
Glucose
Intolerance
120
113
100
80
74
60
40
20
195
Systolic BP (mmHg)
Kannel WB et al. Am Heart J 1991;121:1268-1273.
0
56
48
31
15
105
36
23
135
165
195
Systolic BP (mmHg)
Effect of Glycemic Control in the UK
Prospective Diabetes Study (UKPDS)
Endpoints
Intensive Conventional
(rate/1000 (rate/1000
P
pt yrs)
pt yrs)
%
Decrease
Any diabetes related* 40.9
46
0.029
11
MI
17.4
0.052
16
14.7
Stroke
5.6
5
0.52
–
PVD
1.1
1.6
0.15
–
Microvascular
8.6
11.4
* Combined microvascular and macrovascular events
UKPDS Group. Lancet 1998;352:837-853.
0.0099
25
Reasons for Death in UKPDS Intensive
Treatment Arm: 10-Year Follow-up
N=
2729
(%)
Fatal MI or SD
231
(8.4%)
Cancer
120
(4.4%)
Other
74
(2.9%)
Fatal Stroke
43
(1.6%)
Renal Disease
16
(0.6%)
Accidents
5
(0.2%)
PVD
2
(0.07%)
Hypo- or Hyperglycemia 1
(0.04%)
Accidents, PVD, Hypo& Hyperglycemia
Renal
3.3%
2.5%
15%
Other
24%
Cancer
47%
MI or SD
8.7%
Stroke
UKPDS Group. Lancet 1998;352:837-853.
Effect of Blood Pressure Control in the UKPDS
Tight vs. Less Tight Control
 1,148 Type 2 patients
 Average BP lowered to 144/82 mmHg (controls: 154/87);
9-year follow-up
Tight Control
Risk Reduction (%)
P value
Any diabetes-related endpoint
Diabetes-related deaths
24
32
0.0046
0.019
Heart failure
Stroke
Myocardial infarction
Microvascular disease
56
44
21
37
0.0043
0.013
NS
0.0092
UKPDS Group. BMJ 1998;317:703-713.
UKPDS: ACE Inhibitor vs. Beta-blocker for HTN
Aggregate Clinical Endpoints
Relative Risk & 95% CI
RR
p
Any diabetes-related endpoint 1.10
0.43
Diabetes-related deaths
1.27
0.28
All-cause mortality
1.14
0.44
Myocardial infarction
1.20
0.35
Stroke
1.12
0.74
Microvascular
1.29
0.30
0.5
Favors
ACE inhibitor
UKPDS Group. BMJ 1998;317:713-720.
1
2
Favors
Beta blocker
Systolic Hypertension in Europe (Syst-Eur) Trial:
Events / 1000 Pt-Years
Effect of Systolic BP Control on All Cardiovascular Events
at 2 Years
70
60
50
40
30
20
10
0
57.6
25%
62%
Risk
Reduction
22.0
Placebo
Active Rx
Diabetic Patients
N=492; P=0.002
Tuomilehto J et al. NEJM 1999;340: 677-684.
31.4
Risk
Reduction
23.5
Placebo
Active Rx
Nondiabetic Patients
N=4,203; P=0.02
Major Outcomes of the Hypertension Optimal
Treatment (HOT) Trial: Diabetes Subgroup
Events / 1000 Pt-Years
30
25
Diastolic Target
p<0.005
<90 mmHg (N=501)
<85 mmHg (N=501)
20
<80 mmHg (N=499)
15
p<0.045
10
p<0.016
5
0
Major CV Events
Hansson L et al. Lancet 1998;351: 1755-1762.
MI
CV Mortality
Events / 1000 Pt-Years
HOT Trial:Cardiovascular Events in Diabetics and
Nondiabetics—Effect of Diastolic Target at 4 Years
30
25
20
15
10
24.4
48%
Risk
18.6 Reduction
11.9
5
0
<90
<85
<80
Diabetic Patients
n=1,501; p=0.016
Hansson L et al. Lancet 1998;351: 1755-1762.
9.9
10.0
9.3
<90
<85
<80
Nondiabetic Patients
n=18,790; p=NS
Completed Clinical Trials with
Antihypertensive Agents in Diabetes
Trial
Diabetic/Total
SHEP
583/4736
Beneficial
GISSI-3
2790/18,131
Beneficial
Syst-Eur
492/4695
Beneficial
1501/18,790
Beneficial
UKPDS
1148
Beneficial
CAPPP
572/10,985
Beneficial
HOT
Results on CVD
SHEP = Systolic Hypertension in the Elderly Program; GISSI = Grupo Italiano per lo Studio della Sopravvivenza
nell'Infarto Miocardico; Syst-Eur = Systolic Hypertension in Europe; HOT = Hypertension Optimal Treatment;
CAPPP = Captopril Prevention Project
Curb JD et al. JAMA 1996;276:1886-1892; Zuanetti G et al. Circulation 1997;96:4239-4245; Staessen JA et al.
Am J Cardiol 1998;82:20R-22R; Hansson L et al. Lancet 1998;351:1755-1762;UK Prospective Diabetes Study
Group. BMJ 1998;317:703-713; Hansson L et al. Lancet 1999;353:611-616.
Heart Outcomes Prevention Evaluation (HOPE) Study
Effect of Ramipril on Cardiovascular Events (Myocardial
Infarction, Stroke, or CVD Death) ~ 4.5 Yrs
% of Patients
25
20
15
24%
19.8
Risk
Reduction
15.0
10
21%
16.4
Risk
Reduction
13.0
5
0
Placebo
Ramipril
Diabetic Patients
N=3,578, P=<0.001
Hope Study Investigators. NEJM 2000;342:145-153.
Placebo
Ramipril
Nondiabetic Patients
N=5,719, P=<0.001
Diabetes Increases Risk of Coronary Plaque
Disruption and Thrombosis
Cause of Myocardial Infarction
Platelet Aggregation
F VII
Fibrinogen
F VIII
vWF
Coronary Artery
Thrombus
Plaque
Formation
Plaque
Disruption
Sympathetic Tone
PAI-1
TPA
PGI2
Impact of Serum Fibrinogen and Total Cholesterol
Levels on Risk of Coronary Events in ECAT
7
6
Risk of
Coronary
Events
(%)
Total
Cholesterol
5
4
3
Higher
2
1
Middle
0
Lower
Middle
Fibrinogen
Thompson SG. N Engl J Med 1995;332:635-641.
Lower
Higher
Effect of Aspirin on Mortality in Type 2 Patients with
CHD: Bezafibrate Infarction Prevention Study
Survival (%)
100
OR=0.7 (0.6-0.8)
No
diabetes
90
OR=0.8 (0.7-0.9)
80
Type 2
diabetes
No aspirin
Aspirin
70
0
1
2
3
4
Time (Years)
Harpaz D et al. Am J Med 1998;105:494-499.
5
6
Antiplatelet Agents Reduce CVD Events in
Patients with Diabetes: Antiplatelet
Trialists’ Collaboration
CVD Events (%)
25
P<0.002
Antiplatelet Therapy
Control
20
P<0.00001
15
10
5
0
Diabetes
Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.
No Diabetes
Diabetes Mellitus Insulin Glucose Infusion in Acute
Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic
Control in No Insulin – Low Risk Cohort
Total Cohort
p = .0111
Mortality
0.6
0.7
0.5
Control
0.4
n=306
0.3
0.2
Insulin-glucose
Infusion
0.1
0
0
1
2
3
4
Years in Study
p = .004
0.6
n=314
Mortality
0.7
No Insulin – Low Risk
0.5
n=133
0.4
Control
0.3
0.2
n=139
0.1
5
Malmberg K et al. BMJ 1997;314:1512-1515.
0
0
Insulin-glucose
Infusion
1
2
3
4
Years in Study
5
Effect of Trandolapril on Post-MI CHF Progression:
Trandolapril Cardiac Evaluation (TRACE)
Diabetics (n=237)
0.5
0.5
Placebo
0.4
Event Rate
Event Rate
0.4
0.3
Trandolapril
0.2
0.1
0.0
Nondiabetics (n=1512)
1
2
Years
3
Placebo
0.2
Trandolapril
0.1
Relative risk, 0.38
P<0.001
0
0.3
4
0.0
Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.
Relative risk, 0.81
P = 0.1
0
1
2
Years
3
4
Effect of Trandolapril on Secondary
Endpoints in TRACE
Diabetics
End Point
RR (95% CI)
Interaction
Nondiabetics
P
RR (95% CI)
P
P
Cardiovascular death
0.56 (0.37-0.85)
0.01
0.79 (0.66-0.96)
0.02
0.17
Sudden death
0.46 (0.25-0.85)
0.01
0.84 (0.63-1.12)
0.23
0.09
Reinfarction
0.55 (0.29-1.07)
0.08
0.93 (0.69-1.26)
0.65
0.15
Progression in CHF
0.38 (0.21-0.67)
<0.001
0.81 (0.63-1.04)
0.10
0.03
CI = confidence interval; RR = relative risk.
Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.
Effect of Diabetes on 30-Day Mortality: Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded
Coronary Arteries (GUSTO-I)
2.7
Diabetes vs no diabetes
(unadjusted)
2.1
Adjusted for clinical
variables
2.4
Adjusted for angiographic
variables
2.0
Adjusted for clinical &
angiographic variables
0
1
2
3
4
Odds Ratio for 30-Day Mortality
Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669.
5
Overall 5-Year Mortality in the Bypass Angioplasty
Revascularization Investigation (BARI-1)
1.0
DM-PTCA
Mortality
0.8
DM-CABG
Non DM-CABG
0.6
Non DM-PTCA
0.4
0.25
0.18
0.08
0.07
0.2
0.0
0
1
2
3
Follow-up (years)
Detre KM et al. N Engl J Med 2000;342:989-997.
4
5
Impact of PTCA vs. CABG on Mortality
in BARI-1
Mortality in Patients
without Q-MI
1.0
DM-CABG
0.8
Non DM-CABG
Non DM-PTCA
0.6
Mortality
Mortality
1.0
DM-PTCA
0.8
0.4
0.79
0.6
0.4
0.29
0.27
0.22 0.2
0.16
0.07
0.06
0.2
0.0
Mortality in Patients
After Q-MI
0
1
2
3
4
Follow-up (years)
5
0.0
Detre KM et al. N Engl J Med 2000;342:989-997.
0.17
0
1
2
3
4
Years after Q-MI
5
Impact of Diabetes on 7-year Survival in BARI
All Patients
60
40
CABG (n=914)
20
PTCA (n=915)
0
0
1
2
3
Patients with Treated Diabetes
100
% Survival
84.4
80.9
80
76.4
60
55.7
CABG (n=180)
20
PTCA (n=173)
0
0
1
2
3
4
p = 0.0011
4
5
6
5
6
7
Years
7
Patients without Treated Diabetes
100
80
40
p = 0.0425
% Survival
% Survival
100
86.8
86.4
80
60
40
CABG (n=734)
20
PTCA (n=742)
0
0
1
BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129.
2
3
p = 0.7155
4
5
6
7
Eight-Year Mortality in Emory Angioplasty vs Surgery
Trial (EAST)
All EAST Patients
% Survival
100
80
60
40
CABG (n=194)
20
PTCA (n=198)
0
0
1
2
4
5
60
40
CABG (n=30)
20
PTCA (n=29)
p = 0.23
6
100
% Survival
80
0
3
p = 0.40
Treated Diabetic Patients
100
% Survival
82.7
79.3
7
8
Patients without Diabetes
80
60
40
CABG (n=164)
20
PTCA (n=169)
0
7 8
0 1 2
Years after Randomization
King SB III et al. J Am Coll Cardiol 2000;35:1116-1121.
0
1
2
3
4
5
6
3
4
p = 0.71
5
6
7
8
6-Month Angiographic Outcome after PTCA
in Diabetes (377 Patients with 476 Lesions)
Total Occlusion
100
100
75
75
62%
50
49%
25
Restenosis
(n = 237)
Total
Occlusion
(n = 60)
Patients (%)
Lesions (%)
Overall Restenosis Rate
50
37%
25%
25
11%
0
13%
0
Angiographic FU = 6 months
Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.
1 Site
2 Sites
3 Sites
PTCA Site(s)
Impact of Restenosis and Total Occlusion
on LV Function in Diabetes
15
Restenosis (–)
Restenosis (+)
Total Occlusion (–) Total Occlusion (–)
(n = 297)
(n = 237)
Total Occlusion (+)
(n = 60)
 in EF (%)
10
5
0
-5
-1.5+9.5
+0.5+9.9
-6.2+9.9
-10
-15
-20
p = ns
p = ns
Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.
p = 0.0001
Effect of Stents on Target Vessel
Revascularization (TVR) after PTCA in Diabetes
Proportion Free of TVR
1.00
p = 0.021
df = 3, Log-rank Test
0.95
0.90
0.85
1997
0.80
0.75
0.70
0
0
Year
N
% Stent
1994
305
17.4
1995
425
24.9
1996
480
41.0
1997
288
55.5
2
1996
1995
1994
4
6
8
Months Post PTCA
Rankin JM et al. Circulation 1998;98:I-79.
10
12
Evaluation of Platelet IIb/IIIa Inhibitor for Stenting
Trial (EPISTENT): Benefit of Abciximab and Stenting in
Diabetes on Reducing TVR
20
Stent + Placebo
Stent + Abciximab
Angioplasty + Abciximab
15
18.4%
16.6%
10
8.1%
5
0
0
30
60
90
120 150 180
Patients without Diabetes
(n = 1908)
Incidence of repeated TVR
at 6 mos. (%)
Incidence of repeated TVR
at 6 mos. (%)
Patients with Diabetes
(n = 491)
Days after Randomization
Lincoff AM et al. N Engl J Med 1999;341:319-327.
20
Stent + Placebo
Stent + Abciximab
Angioplasty + Abciximab
15
14.6%
9.0%
10
8.8%
5
0
0
30
60
90
120 150 180
Days after Randomization
EPISTENT: Optimization of PTCA/Stent
Outcomes with Platelet IIb/IIIa Inhibition
6-Month Death, MI for Diabetics
15
% of Patients
12.7%
p = 0.029
10
7.8%
6.2%
5
0
Stent + Placebo
Stent + Abciximab
PTCA + Abciximab
0
30
60
90
Days
Marso SP et al. Circulation 1999;100:2477-2484.
120
150
180
Conclusions
In patients with diabetes mellitus, there are numerous opportunities
to reduce morbidity and mortality from CAD:
 identify diabetic patients with particularly high risk for CAD and perform
appropriate screening
 aggressively identify and modify coronary risk factors
 explore and implement treatment to protect the left ventricle from
ischemic injury
 maintain tight but judicious glycemic control in acute coronary
syndromes
 use medications proven to dramatically improve outcomes in acute MI
(beta blockers, ACE inhibitors, aspirin, IIb/IIIa platelet inhibitors, statins)
Future Directions
 Additional clinical trials are needed to evaluate
cardiovascular therapeutic interventions in diabetic
patients, because certain therapies may produce
different results in the presence of diabetes