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