1、Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic Patient Richard Nesto, MD,Prevalence of Asymptomatic CAD in Diabetes Mellitus,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 Cardio
2、l 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,n = 64 n = 72 n = 80n = 142 n = 149n = 925n = 43 n = 43,P
3、ositive ETT,Positive Angiography,(thal201),36% 24% 9%31% 30%12.1%65% 40%58%55%,9% 11% 9%12.1% 5.3%6.4% 35%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 Se
4、dentary 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 140/90 mmHg- Smoking- Family history of premature CAD- Positive micro/macroalbuminuria,Factors Limiting Accuracy of
5、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 w
6、ould benefit from revascularization Educate patients to recognize coronary symptoms,Kannel WB et al. Am Heart J 1991;121:1268-1273.,Blood Pressure and CVD: Framingham Heart Study,Age-adjusted CV Event Rate/1,000,Systolic BP (mmHg),105,135,165,195,Systolic BP (mmHg),105,135,165,195,Age-adjusted CV Ev
7、ent Rate/1,000,24,50,38,77,59,119,90,174,15,31,23,48,36,74,56,113,No Glucose Intolerance Glucose Intolerance,No Glucose Intolerance Glucose Intolerance,MEN,WOMEN,UKPDS Group. Lancet 1998;352:837-853.,Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS),Any diabetes related* MI Str
8、oke PVD Microvascular,40.9 14.7 5.6 1.1 8.6,46 17.45 1.6 11.4,0.029 0.052 0.52 0.15 0.0099,11 16 25,(rate/1000 pt yrs),* Combined microvascular and macrovascular events,Intensive,% Decrease,(rate/1000 pt yrs),P,Conventional,Endpoints,Reasons for Death in UKPDS Intensive Treatment Arm: 10-Year Follow
9、-up,UKPDS Group. Lancet 1998;352:837-853.,47%,8.7%,24%,15%,3.3%,2.5%,MI or SD,Cancer,Stroke,Other,Renal,Accidents, PVD, Hypo- & Hyperglycemia,UKPDS Group. BMJ 1998;317:703-713.,Effect of Blood Pressure Control in the UKPDS Tight vs. Less Tight Control,Any diabetes-related endpoint Diabetes-related d
10、eaths Heart failure Stroke Myocardial infarction Microvascular disease,Tight Control,1,148 Type 2 patients Average BP lowered to 144/82 mmHg (controls: 154/87); 9-year follow-up,24 32 56 44 21 37,Risk Reduction (%),P value,0.0046 0.019 0.0043 0.013NS 0.0092,UKPDS: ACE Inhibitor vs. Beta-blocker for
11、HTN Aggregate Clinical Endpoints,0.5,1,2,Relative Risk & 95% CI,Any diabetes-related endpoint Diabetes-related deaths All-cause mortality Myocardial infarction Stroke Microvascular,1.10 1.27 1.14 1.20 1.12 1.29,0.43 0.28 0.44 0.35 0.74 0.30,p,RR,UKPDS Group. BMJ 1998;317:713-720.,Favors ACE inhibito
12、r,Favors Beta blocker,Placebo,Events / 1000 Pt-Years,Systolic Hypertension in Europe (Syst-Eur) Trial: Effect of Systolic BP Control on All Cardiovascular Events at 2 Years,Tuomilehto J et al. NEJM 1999;340: 677-684.,N=492; P=0.002,Active Rx,57.6,22.0,62% Risk Reduction,N=4,203; P=0.02,31.4,23.5,Pla
13、cebo,Active Rx,25% Risk Reduction,Diabetic Patients,Nondiabetic Patients,Major CV Events,MI,Events / 1000 Pt-Years,Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup,Hansson L et al. Lancet 1998;351: 1755-1762.,CV Mortality,90 mmHg (N=501) 85 mmHg (N=501) 80 mmHg (N=
14、499),Diastolic Target,p0.045,p0.016,p0.005,90,Events / 1000 Pt-Years,HOT Trial:Cardiovascular Events in Diabetics and NondiabeticsEffect of Diastolic Target at 4 Years,Hansson L et al. Lancet 1998;351: 1755-1762.,Diabetic Patients n=1,501; p=0.016,85,80,90,85,80,Nondiabetic Patients n=18,790; p=NS,2
15、4.4,18.6,11.9,9.9,10.0,9.3,48% Risk Reduction,Completed Clinical Trials with Antihypertensive Agents in Diabetes,SHEP = Systolic Hypertension in the Elderly Program; GISSI = Grupo Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico; Syst-Eur = Systolic Hypertension in Europe; HOT = Hyp
16、ertension 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
17、-713; Hansson L et al. Lancet 1999;353:611-616.,SHEP GISSI-3 Syst-Eur HOT UKPDS CAPPP,Results on CVD,Diabetic/Total,Trial,583/4736 2790/18,131 492/4695 1501/18,790 1148 572/10,985,Beneficial Beneficial Beneficial Beneficial Beneficial Beneficial,Heart Outcomes Prevention Evaluation (HOPE) Study Effe
18、ct of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) 4.5 Yrs,Hope Study Investigators. NEJM 2000;342:145-153.,Placebo,% of Patients,Ramipril,19.8,15.0,24% Risk Reduction,16.4,13.0,Placebo,Ramipril,21% Risk Reduction,Diabetic Patients,Nondiabetic Patients,N=3,578, P=0
19、.001,N=5,719, P=0.001,Diabetes Increases Risk of Coronary Plaque Disruption and Thrombosis Cause of Myocardial Infarction,Plaque Formation,F VII,F VIII,Coronary Artery,Sympathetic Tone,PAI-1 TPA PGI2,Platelet Aggregation Fibrinogen vWF,Thrombus,Plaque Disruption,Impact of Serum Fibrinogen and Total
20、Cholesterol Levels on Risk of Coronary Events in ECAT,Thompson SG. N Engl J Med 1995;332:635-641.,Fibrinogen,Lower,Middle,Higher,Higher,Middle,Lower,Total Cholesterol,Risk of Coronary Events (%),4/306,9/261,10/282,5/311,3/247,10/281,11/266,16/304,21/305,Effect of Aspirin on Mortality in Type 2 Patie
21、nts with CHD: Bezafibrate Infarction Prevention Study,Harpaz D et al. Am J Med 1998;105:494-499.,Survival (%),No diabetes,Type 2 diabetes,Time (Years),0,1,2,3,4,5,6,No aspirin Aspirin,OR=0.8 (0.7-0.9),OR=0.7 (0.6-0.8),Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Tria
22、lists Collaboration,Antiplatelet Trialists Collaboration. BMJ 1994;308:81-106.,CVD Events (%),Diabetes,Antiplatelet Therapy Control,No Diabetes,P0.002,P0.00001,Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin Low Risk
23、 Cohort,Malmberg K et al. BMJ 1997;314:1512-1515.,0.7 0.6 0.5 0.4 0.3 0.2 0.1 0,0.7 0.6 0.5 0.4 0.3 0.2 0.1 0,Mortality,Mortality,Total Cohort,No Insulin Low Risk,Years in Study,Years in Study,Control,Insulin-glucose Infusion,Insulin-glucose Infusion,Control,p = .0111,p = .004,n=133,n=139,n=314,n=30
24、6,Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE),Years,Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.,Diabetics (n=237),0,1,2,3,4,Event Rate,Years,Nondiabetics (n=1512),0,1,2,3,4,Event Rate,Relative risk, 0.38 P0.001,Relative risk, 0.81 P = 0.1,Place
25、bo,Trandolapril,Placebo,Trandolapril,Cardiovascular death Sudden death Reinfarction Progression in CHF,Diabetics RR (95% CI) P,End Point,Effect of Trandolapril on Secondary Endpoints in TRACE,0.56 (0.37-0.85) 0.46 (0.25-0.85) 0.55 (0.29-1.07) 0.38 (0.21-0.67),0.79 (0.66-0.96) 0.84 (0.63-1.12) 0.93 (
26、0.69-1.26) 0.81 (0.63-1.04),0.17 0.09 0.15 0.03,Nondiabetics RR (95% CI) P,Interaction P,CI = confidence interval; RR = relative risk.,Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.,0.01 0.01 0.08 0.001,0.02 0.23 0.65 0.10,Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669.,Effect of Diab
27、etes on 30-Day Mortality: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I),2.7,2.1,2.4,2.0,0,1,2,3,4,5,Odds Ratio for 30-Day Mortality,Diabetes vs no diabetes (unadjusted) Adjusted for clinical variables Adjusted for angiographic variables
28、 Adjusted for clinical & angiographic variables,Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1),Detre KM et al. N Engl J Med 2000;342:989-997.,0,Mortality,DM-PTCA DM-CABG Non DM-CABG Non DM-PTCA,Follow-up (years),0.25,0.18,0.08,0.07,1,2,3,4,5,Impact of PTC
29、A vs. CABG on Mortality in BARI-1,Mortality,Follow-up (years),Years after Q-MI,DM-PTCA DM-CABG Non DM-CABG Non DM-PTCA,Mortality,Mortality in Patients without Q-MI,Mortality in Patients After Q-MI,0.22,0.16,0.07,0.06,0.79,0.29,0.27,0.17,Detre KM et al. N Engl J Med 2000;342:989-997.,Impact of Diabet
30、es on 7-year Survival in BARI,BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129.,% Survival,Years,Patients without Treated Diabetes,% Survival,All Patients,% Survival,Patients with Treated Diabetes,p = 0.0425,p = 0.7155,p = 0.0011,CABG (n=914) PTCA (n=915),CABG (n=180) PTCA (n=173),CABG (n=734
31、) PTCA (n=742),84.4,80.9,76.4,55.7,86.8,86.4,Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST),King SB III et al. J Am Coll Cardiol 2000;35:1116-1121.,% Survival,Years after Randomization,Patients without Diabetes,% Survival,All EAST Patients,% Survival,Treated Diabetic Patients,p =
32、0.40,p = 0.71,p = 0.23,CABG (n=194) PTCA (n=198),CABG (n=30) PTCA (n=29),CABG (n=164) PTCA (n=169),82.7,79.3,6-Month Angiographic Outcome after PTCA in Diabetes (377 Patients with 476 Lesions),Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.,Lesions (%),Angiographic FU = 6 months,62%,PTCA Site(
33、s),1 Site,2 Sites,3 Sites,Overall Restenosis Rate,Total Occlusion,49%,13%,Restenosis (n = 237) Total Occlusion (n = 60),Patients (%),11%,25%,37%,Impact of Restenosis and Total Occlusion on LV Function in Diabetes,Van Belle E et al. J Am Coll Cardiol 1999;34:476-485., in EF (%),p = ns,p = ns,p = 0.00
34、01,(n = 297),(n = 237),(n = 60),Restenosis () Total Occlusion (),Restenosis (+) Total Occlusion (),Total Occlusion (+),-1.5+9.5,+0.5+9.9,-6.2+9.9,Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in Diabetes,1.00 0.95 0.90 0.85 0.80 0.75 0.70 0,Proportion Free of TVR,p = 0.021 df
35、= 3, Log-rank Test,Rankin JM et al. Circulation 1998;98:I-79.,Months Post PTCA,0,2,4,6,8,10,12,Year 1994 1995 1996 1997,1997,1996,1995,1994,N 305 425 480 288,% Stent 17.4 24.9 41.0 55.5,Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Benefit of Abciximab and Stenting in Diab
36、etes on Reducing TVR,Lincoff AM et al. N Engl J Med 1999;341:319-327.,Days after Randomization,Stent + Placebo Stent + Abciximab Angioplasty + Abciximab,Patients with Diabetes (n = 491),Incidence of repeated TVR at 6 mos. (%),Days after Randomization,Patients without Diabetes (n = 1908),Incidence of
37、 repeated TVR at 6 mos. (%),18.4%,16.6%,8.1%,14.6%,Stent + Placebo Stent + Abciximab Angioplasty + Abciximab,9.0%,8.8%,% of Patients,Days,EPISTENT: Optimization of PTCA/Stent Outcomes with Platelet IIb/IIIa Inhibition,Marso SP et al. Circulation 1999;100:2477-2484.,12.7%,7.8%,6.2%,0,30,90,120,180,60
38、,150,6-Month Death, MI for Diabetics,Stent + Placebo Stent + Abciximab PTCA + Abciximab,p = 0.029,Conclusions,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 pro
39、tect 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),In patients with diabetes mellitus, there are numerous opportunities to reduce morbidity and mortality from CAD:,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,
