Diabetes and Cardiovascular Disease:
The Role of the Glycoprotein llb/llla Inhibitors
A. Michael Lincoff, MD, FACC, Editor
Associate Professor of Medicine
Department of Cardiovascular Medicine
Joseph J. Jacobs Center for Thrombosis and Vascular Biology
The Cleveland Clinic Foundation
Cleveland, Ohio
This activity has been prepared under the direction of
Samuel S. Engel, MD, Reviewer
Associate Clinical Professor of Medicine
Diabetes Research Center
Albert Einstein College of Medicine
Bronx, New York
MI
incidence
55
50
45
40
35
30
25
20
15
10
5
0
No MI
45†
Prior MI
18.8†
20.2
3.5
Non-DM
(N=1373)
Diabetes*
(N=1059)
*p<0.001 for diabetes vs no diabetes.
†p<0.001 for prior MI vs no prior MI.
Figure 1. Incidence of fatal or nonfatal myocardial infarction (MI) during 7-year follow-up in
diabetic and nondiabetic subjects with and without prior MI. Events/100 person-years. Data
from Haffner SM et al 1998.5
55
45
40
Men
Women
35
30
Prevalence
25
(%)
20
15
10
5
0
20–29
30–39
40–49
50–59
60–69
≥70
Age (yr)
Figure 2. Age-specific prevalence of the metabolic syndrome among 8814 US adults aged
20 years (± SE). National Health and Nutrition Examination Survey III, 1988-1994.
Reprinted with permission from Ford ES et al.20
Nondiabetics
Diabetics
Figure 3. Maladaptive arterial remodeling in diabetes mellitus. In nondiabetic persons, as the
atherosclerotic lesion enlarges, due to increasing deposition of lipid and smooth muscle cell
proliferation, it does not immediately encroach on the lumen but enlarges outward. Only when
approximately 40% of the lesion is filled with plague does the lumen narrow. In diabetic
persons, however, insulin treatment results in a greater impact of plaque accumulation on
lumen compromise, probably as a result of a blunted adaptive modeling response. Data from
Kornowski R et al.21
EMORY
MAHI
All Insulin
DM req. DM
Hazard
ratio
(5-6 yr
follow-up)
CABG 2
better
DUKE
BARI
Registry
NNE
BARI
Randomized
*
1
PCI
better
N
Enrollment period
CABG patients
with 3VD (%)
PCI patients
with 3VD (%)
2639
1981-94
63
24
2776
525
770
299
353
1987-90 1984-90 1988-91 1992-96 1988-91
56
85
61
60
48
52
22
35
16
44
*Unadjusted.
Figure 4. Diabetes survival after revascularization. Hazard ratios and 95% confidence
intervals at 5- to 6–year follow-up for initial percutaneous coronary intervention (PCI) compared
with coronary artery bypass graft (CABG) among patients with diabetes mellitus (DM) and
multivessel disease estimated from three database studies, the BARI registry, NNE, and the
BARI randomized trial. All hazard ratios are adjusted, except MAHI. BARI=Bypass
Angioplasty Revascularization Investigation, MAHI=Mid America Heart Institute, NNE=Northern
New England database study; 3VD=3-vessel disease. Reprinted with permission from Niles
NW et al.25
100
p<0.0001
90
80
70
%
Survival
60
50
40
30
No restenosis, n=162
Nonocclusive restenosis, n=257
Occlusive restenosis, n=94
20
10
0
0
1
2
3
4
5
6
7
8
9
10
Years
Figure 5. Late vessel occlusion in diabetes mellitus. Kaplan-Meier survival curves for longterm total mortality as a function of vessel patency at repeated angiography in dilated
vessels. Number of patients = 513; mean follow-up 6.5±2.4 years. Reprinted with
permission from Van Belle E et al.9
Figure 6. Macrophage infiltration of diabetic atheromata. Photomicrographs of coronary
atherectomy tissue immunostained with antihuman pan-macrophage antibody. Macrophage
content seen in coronary tissue from a patient with diabetes mellitus (DM) (A) is larger than
from a patient without DM (B). Reprinted with permission from Moreno PR et al.4
Increased:
Fibrinogen
von Willebrand factor
Increased:
Platelet numbers
Platelet volume
Increased GP IIb/IIIa
receptor:
Density
Activation/affinity
Figure 7. Role of glycoprotein (GP) llb/llla in platelet aggregation. Receptor function of GP
llb/llla for soluble fibrinogen and von Willebrand factor (vWF) manifests after platelet stimulation.
Unstimulated, discoid platelets are depicted with receptors for thrombin, adenosine diphosphate
(ADP), collagen, vWF, and immobilized fibrinogen, any of which may stimulate platelets, inducing
a change in their shape and activating the receptor function of GP llb/llla. Reprinted with
permission from Scarborough RM et al.62
30
Stent + placebo
Stent + abciximab
Balloon + abciximab
25
20
25.2%
23.4%
%
of patients 15
13.0%
10
5
p=0.005
0
0
30
60
90
120
150
180
Days
Figure 8. Results of the Evaluation of Platelet llb/llla Inhibition for Stenting (EPISTENT)
diabetic substudy. Figure shows the 6-month combined death, myocardial infarction (MI), and
target vessel revascularization (TVR) rates for diabetic patients. There was a significant
reduction in the 6-month combined event rate of death, MI, or TVR for the stent-abciximab
group compared with both the stent-placebo and percutaneous transluminal coronary
angioplasty-abciximab groups. Reprinted with permission from Marso SP et al.84
20
18.4%
16.6%
Stent + placebo
Stent + abciximab
PTCA + abciximab
15
%
of patients 10
8.1%
5
p=0.021
0
0
30
60
90
120
150
180
Days
Figure 9. Reduction in the 6-month target vessel revascularization rate for stent-abciximab
patients compared with stent-placebo and balloon-abciximab patients among treated diabetic
patients in the EPISTENT substudy. PTCA=percutaneous transluminal coronary angiolplasty.
Reprinted with permission from Marso SP et al.84
6
Diabetes/abciximab (n=888)
Diabetes/placebo (n=574)
No Diabetes/abciximab (n=3222)
No Diabetes/placebo (n=1850)
5
4
4.5%
Death 3
(%)
2
2.6%
2.5%
1.9%
1
p=0.031
0
0
30
60
90 120 150 180 210 240 270 300 330 360
Days from Randomization
Figure 10. Pooled data from 3 placebo-controlled trials in percutaneous coronary intervention:
the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC), the Evaluation of
PTCA to Improve Long-Term Outcomes with Abciximab GP llb/llla Blockade (EPILOG), and the
Evaluation of Platelet llb/llla Inhibitor for Stenting (EPISTENT). The 1-year mortality rate for
patients with diabetes mellitus was compared with the rate for nondiabetic patients treated with
abciximab or placebo. Figure show Kaplan-Meier curves for 1-year mortality in patients with
and without diabetes randomized to either placebo or abciximab. Reprinted with permission
from Bhatt DL et al.82
B.
Placebo (n=65)
Abciximab (n=108)
8
IDDM/placebo (n=197)
IDDM/abciximab (n=265)
9
8
7
6
5
4
3
2
1
0
7
8.1%
7.7%
6
4.2%
p=0.073
0
50 100 150 200 250 300 350
Days from Randomization
Death (%)
Death (%)
A.
5
4
3
p=0.018
2
1
0
0.9%
0
50 100 150 200 250 300 350
Days from Randomization
Figure 11. Kaplan-Meier curves for 1-year mortality in the Evaluation of c7E3 for the
Prevention of Ischemic Complications (EPIC), the Evaluation of PTCA to Improve Long-Term
Outcomes with Abciximab GP llb/llla Blockade (EPILOG), and the Evaluation of Platelet llb/llla
Inhibitor for Stenting (EPISTENT) in 2 subgroups of diabetic patients. (A) A mortality reduction
was noted in the insulin-dependent diabetic patients with abcximab treatment. (B) Mortality was
also reduced with abciximab treatment vs placebo in stented patients who underwent
multivessel intervention. Reprinted with permission from Bhatt DL et al.11
B.
A.
Trial
N
Odds Ratio and 95% CI
Placebo IIb/IIIa
Trial
N
Odds Ratio and 95% CI Placebo IIb/IIIa
2163
p=0.33
6.1% 5.1%
PURSUIT
457
3.3% 2.4%
687
p=0.07
p=0.57
4.2% 1.8%
PRISM
147
2.5% 0.0%
PRISM-PLUS 362
p=0.17
p=0.50
6.7% 3.6%
PRISM-PLUS 107
p=1.00
1.8% 0.0%
GUSTO IV
GUSTO IV
239
p=0.037
6.5% 1.2%
45
p=0.31
7.1% 0.0%
PARAGON B 1157
p=0.022 7.8% 5.0%
p=0.51
6.2% 4.6%
p=0.93
4.8% 4.9%
PARAGON B 284
p=0.06
4.3% 0.7%
Pooled
p=0.007 6.2% 4.6%
Pooled
p=0.002
4.0% 1.2%
PURSUIT
PRISM
1677
PARAGON A 412
6458
0
Breslow-Day: p=0.50
0.5
IIb/IIIa
Better
1
1.5
2
Placebo
Better
PARAGON A
1279
0
NNT=63
Breslow-Day: p=0.46
0.5
IIb/IIIa
Better
1
1.5
Placebo
Better
2
NNT=36
Figure 12. Results of a meta-analysis of the diabetic populations in the 6 large-scale platelet
glycoprotein llb/llla inhibitor acute coronary syndrome (ACS) trials. (A) Treatment effect on 30-day
mortality in patients with diabetes mellitus (DM) and ACS. (B) Treatment effect on 30-day morality in
patients with DM treated with percutaneous coronary intervention. Values to left of 1.0 indicate a
survival benefit of platelet GP llb/llla inhibition. CI=confidence interval, GUSTO IV=the Global Use of
Strategies to Open Occluded Coronary Arteries, NNT=number needed to treat, PARAGON A &
B=Platelet llb/llla Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global
Organization Network, PRISM=Platelet Receptor Inhibition in Ischemic Syndrome Management,
PRISM-PLUS=Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by
Unstable Signs and Symptoms, PURSUIT=Platelet Glycoprotein llb/llla in Unstable Angina: Receptor
Suppression Using Integrilin Therapy. Reprinted with permission form Roffi M et al. 89
30
25
p=0.003
20
Macrophage
area
(%)
15
10
5
0
Diabetes
No diabetes
Figure 13. Macrophage infiltration of diabetic atheromata. Increased percent area (mean ±
SEM) of macrophages in coronary tissue from patients with diabetes mellitus (DM) vs tissue
from patients without DM. Reprinted with permission from Moreno PR et al.4
8
Change in CRP (mg/dL)
6
4
2
0
–2
–4
Plac Abcix
24-48 h
p=0.025
Plac Abcix
4 wk
p=0.06
Figure 14. Systemic markers of inflammation increase in the first 24 to 48 hours
postangioplasty, but the magnitude of the rise is diminished by periprocedural abciximab. The
figure shows changes in levels of C-reactive protein (CRP) 24-48 hours and 4 weeks after
administration of abciximab bolus plus infusion, relative to baseline levels. The box spans the
25th to 75th percentiles; the line within the box denotes the median; the square denotes the
mean. Reprinted with permission from Lincoff AM et al.99
80
70
60
50
Apoptotic
index
40
30
*
20
10
0
Monocytes
-
+
+
+
+
M-CSF
-
+
+
+
+
Figure 15. Effect of GP: llb/llla blockers on macrophage colony-stimulating factor (M-CSF)triggered, monocyte-induced apoptosis of vascular smooth muscle cells. At therapeutic
concentrations, abciximab (7 g/mL) produces a significant decrease in apoptosis (p<0.0003,
relative to identical conditions with no abciximab). Eptifibatide (5 g/mL) and tirofiban (0.35
g/mL) do not produce this protective effect. Reprinted with permission from Seshiah PN et al.95
Table 1. ARTS TRIAL: 1-Year Outcomes
No Diabetes
Diabetes
Stent
(n=112)
CABG
(n=96)
Death, n(%)
7 (6.3)
Cerebrovascular events, n(%)
p-value
Stent
(n=488)
3(3.1)
0.294
8(1.6)
14 (2.8)
0.412
2 (1.8)
6 (6.3)
0.096
7 (1.4)
6 (1.2)
0.722
MI, n (%)
7 (6.3)
3 (3.1)
0.294
25 (5.1)
21 (4.1)
0.453
Q-wave MI, n (%)
6 (5.4)
2 (2.1)
0.222
22 (4.5)
20 (3.9)
0.649
CABG, n (%)
9 (8.0)
0
<0.001
19 (3.9)
3 (0.6) <0.001
PTCA, n (%)
16 (14.3)
3 (3.1)
<0.001
57 (11.7)
15 (2.9) <0.001
Event-free, n (%)
71 (63.4)
81 (84.4)
<0.001
372 (76.2)
450 (88.4) <0.001
CABG
(n=509) p-value
Repeat revascularization*
ART=the Aterial Revascularization Therapy Study, CABG=coronoary atery bypass graft,
MI=myocardial infarction, PTCA=percutaneous transluminal coronary angioplasty.
Reprinted with permission from Abizaid A et al.27
Table 2. Insulin Resistance is Associated With an Atherogenic Lipid Profile
Insulin-Sensitive Subjects Insulin-Resistant Subjects
(n=37)
(n=442)
p-value
Lipids (mg/dL)
Total cholesterol
220.2 ± 7.3
215.2 ± 2.3
0.507
LDL cholesterol
145.7 ± 6.0
140.4 ± 2.0
0.403
HDL cholesterol
45.3 ± 1.7
39.5 ± 0.6
0.001
VLDL cholesterol
20.5 ± 3.1
26.5 ± 1.3
0.033
Total triglyceride
133 ± 14.4
166 ± 5.8
0.019
VLDL triglyceride
87.2 ± 13.3
122.4 ± 5.8
0.004
Reprinted with permission from Haffner SM et al.41