1、LIPID: Reduction in Nonfatal MI and CHD Death Risk Stratified by Diabetic Status,-19,-25,30,25,20,15,10,5,0,With diabetes Without diabetes(n=782) (n=8,232),LIPID Study Group. N Engl J Med. 1998;339:1349-1357.,%,0,1,2,3,CHD mortality (per 1,000),Fontbonne AM et al. Diabetes Care. 1991;14:461-469.,29
2、30-50 51-72 73-114 115,Quintiles (pmol) of fasting plasma insulin,P0.01,CHD Mortality and Hyperinsulinemia: Paris Prospective Study (n=943),0,10,20,30,40,50,60,1,2,3,4,5,% Macrovascular disease,P,0.001,0,10,20,30,40,50,60,70,80,1,2,3,4,5,% Macrovascular disease,P,0.05,0,10,20,30,40,50,60,1,2,3,4,5,%
3、 CHD,P,0.002,0,10,20,30,40,50,60,70,80,1,2,3,4,5,% CHD,Nondiabetic controls (n=178),Noninsulin-treated type 2 diabetics (n=154),Fasting C-peptide quintiles (1-5),Janka HU. Horm Metab Res. 1985;15(suppl):15-19.,Prevalence of Macrovascular Disease and CHD According to Quintiles of Fasting C-Peptide,Fi
4、nnish Diabetes Prevention Study: Treating the IGT* Patient With Lifestyle Changes,Study Design 522 middle-aged, overweight subjects 172 men, 350 women with IGT BMI 31 kg/m2 mean age: 55 years mean duration: 3.2 years intervention group: individualized counseling reducing weight, total intake of fat
5、and saturated fat increasing intake of fiber, physical activity,*Plasma glucose concentration of 140 to 200 mg/dL. BMI 25 kg/m2. IGT=impaired glucose tolerance; BMI=body mass index. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.,Finnish Diabetes Prevention Study: Success in Achieving Treatmen
6、t Goals at 1 Year,*P values were determined for the difference between groups. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.,Finnish Diabetes Prevention Study: Reduction in Risk for Diabetes*,Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.,11%,23%,0,5,10,15,20,25,Intervention,Control,(
7、n=265),(n=257),*P0.001; 4-year results,Diabetes (%),BMI=body mass index. DPP Research Group. N Engl J Med. 2002;346:393-403.,Diabetes Prevention Program: Study Design,Entry Criteria age 25 years BMI 24 kg/m2 (22 kg/m2 in Asians) fasting plasma glucose 95-125 mg/dL postglucose challenge 140-199 mg/dL
8、 Intervention standard lifestyle recommendations + placebo twice daily standard lifestyle recommendations + metformin titrated to 850 mg twice daily intensive lifestyle modification (low-calorie/low-fat diet, moderate physical activity 150 min/wk) troglitazone (later withdrawn) Outcome type 2 diabet
9、es over average follow-up of 2.8 years,DAIS: Impact of Aggressive Therapy on Atherosclerosis in Patients With Type 2 Diabetes,Study population N=418 (305 men, 113 women) Type 2 diabetes 1 minimal lesion on angiography Mild elevations of LDL-C or TG + TC:HDL-C 4 Treatment 8 weeks on Step I diet Rando
10、mized, blinded to micronized fenofibrate (200 mg/d) and placebo Primary end point Progression or regression of CAD on quantitative angiography,DAIS=Diabetes Atherosclerosis Intervention Study. Steiner G et al. Am J Cardiol. 1999;84:1004-1010.,Garber AJ. Clin Cornerstone. 2003;5:22-37. Garber AJ. Med
11、 Clin North Am. 1998;82:931-948. National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.,Atherosclerosis in Diabetes,Accelerated atherosclerosis is multifactorial and begins years/decades prior to diagnosis of type 2 diabetes 50% of patients with newly diagnosed type 2 diabetes have CHD
12、 Risk for atherosclerotic events is 2- to 4-fold greater in diabetics than in nondiabetics Atherosclerosis accounts for 65% of all diabetic mortality 40% due to ischemic heart disease 15% due to other heart disease 10% due to cerebrovascular disease,Framingham Heart Study 30-Year Follow-Up: CVD Even
13、ts in Patients With Diabetes (Ages 35-64),10,9,20,11,9,6,38,19,3*,30,0,2,4,6,8,10,Age-adjusted annual rate/1,000,Men,Women,Total CVD,CHD,Cardiac failure,Intermittent claudication,Stroke,Risk ratio,P0.001 for all values except *P0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Di
14、sease. Ruderman N et al, eds. Oxford; 1992.,Kannel WB. Am Heart J. 1985;110:1100-1107. Abbott RD et al. JAMA. 1988;260:3456-3460.,Women, Diabetes, and CHD,Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal risk of recurrent MI in diabe
15、tic women is three times that of nondiabetic women Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women,7.4,3.3,10.5,3.4,0,5,10,15,Type 2 (n=135),Others (n=3,946),Type 2 on placebo (n=76),Type 2 on gemfibrozil (n=59),5-Yr incidence of
16、 CHD (%),*Myocardial infarction or cardiac death. NS=not significant.Koskinen P et al. Diabetes Care. 1992;15:820-825.,P0.02,P=NS,Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study,Haffner SM et al. N Engl J Med. 1998;339:229-234.,0,1,2,3,4,5,6,7,8,0,20,40,60,80,100,N
17、ondiabetic subjects without prior MI (n=1,304) Diabetic subjects without prior MI (n=890) Nondiabetic subjects with prior MI (n=69) Diabetic subjects with prior MI (n=169),Survival (%),Year,Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI,Secondary
18、Prevention: CHD Risk Reduction in the 4S Subgroup of Patients With Diabetes,Pyrl K et al. Diabetes Care. 1997;20:614-620.,0.60,0.70,0.80,0.90,1.00,4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes,Pyrl K et al. Diabetes Care. 1997;20:614-620.,Proportion alive,Yr since randomizati
19、on,- P=0.08,- P=0.001,Diabetic, simvastatin,Diabetic, placebo,Nondiabetic, simvastatin,Nondiabetic, placebo,29%,43%,4S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes,Pyrl K et al. Diabetes Care. 1997;20:614-620.,Proportion without major CHD event,Yr since randomization,- P=0.002,
20、- P=0.0001,Diabetic, simvastatin,Diabetic, placebo,Nondiabetic, simvastatin,Nondiabetic, placebo,32%,55%,WOSCOPS: Development of Type 2 Diabetes,Kaplan-Meier plots of time to development of type 2 diabetes according to treatment assignment.Freeman DJ et al. Circulation. 2001;103:357-362.,% diabetic,
21、Years in study,0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5,6 5 4 3 2 1 0,Placebo Pravastatin 40 mg/d,Steno-2: Effect of Therapies on Selected Risk Factors,Gaede P et al. N Engl J Med. 2003;348:383-393.,0,5,6,7,8,9,10,11,0,1,2,3,4,5,6,7,8,0,110,120,130,140,150,160,170,0,1,2,3,4,5,6,7,8,0,65,70,75,80,85,90,95
22、,0,1,2,3,4,5,6,7,8,SBP (mm Hg),HbA1c (%),Follow-up (yr),Conventional therapy,Intensive therapy,Intensive therapy,Conventional therapy,Conventional therapy,Intensive therapy,DBP (mm Hg),0,50,100,150,200,250,300,350,0,1,2,3,4,5,6,7,8,0,50,75,100,125,150,175,200,0,1,2,3,4,5,6,7,8,0,50,100,150,200,250,3
23、00,350,0,1,2,3,4,5,6,7,8,TG (mg/dL),LDL-C (mg/dL),TC (mg/dL),Follow-up (yr),Conventional therapy,Intensive therapy,Intensive therapy,Conventional therapy,Intensive therapy,Conventional therapy,Steno-2: Primary Composite End Point or Surgery for PAD,Gaede P et al. N Engl J Med. 2003;348:383-393.,No.
24、at Risk Conventional tx 80 72 70 63 59 50 44 41 13 Intensive tx 80 78 74 71 66 63 61 59 19,Follow-up (mo),0 12 24 36 48 60 72 84 96,60,50,40,30,20,10,0,Conventional therapy,Intensive therapy,P = 0.007,%,PAD=peripheral artery disease.,(log-rank test),%,HPS Substudy: First Major Vascular Event in Pati
25、ents With Diabetes,Follow-up (years),Placebo,Simvastatin,Benefit/1,000,-1,13,34,47,51,58,P0.0001,0,1,2,3,4,5,6,0,5,10,15,20,25,30,HPS Collaborative Group. Lancet. 2003;361:2005-2016.,HPS Substudy: First Major Coronary Event and Stroke by Prior Diabetes Status,Simvastatin (10,269),Placebo (10,267),Ra
26、te ratio (95% CI),Statin better,Placebo better,Vascular event & diabetes status,Major coronary event,With diabetes,279 (9.4%),377 (12.6%),No diabetes,619 (8.5%),835 (11.5%),All patients,898 (8.7%),1,212 (11.8%),27% reduction (P0.0001),Stroke,With diabetes,149 (5.0%),193 (6.5%),No diabetes,295 (4.0%)
27、,392 (5.4%),All patients,444 (4.3%),585 (5.7%),25% reduction (P0.0001),0.4,0.6,0.8,1.0,1.2,1.4,Any major vascular event (including revascularizations),2,033 (19.8%),2,585 (25.2%),24% reduction (P0.0001),HPS Collaborative Group. Lancet. 2003;361:2005-2016.,Risk reductions:,HPS Diabetes Substudy: Abso
28、lute Effects on 5-Year Rates of First Major Vascular Event,40,Proportion (%),Proportional,Absolute/1,000,P value,32.9% 44 0.0003,24.5% 62 0.0001,18.4% 66 0.002,20%,25%,31%,36%,S,S,S,P,P,P,30,20,10,0,S=simvastatin P=placebo,HPS Collaborative Group. Lancet. 2003;361:2005-2016.,Gould AL et al. Circulat
29、ion. 1998;97:946-952.,Clinical Benefits of Cholesterol Reduction,A recent meta-analysis of 38 trials demonstrated that for every 10% reduction in TC CHD mortality decreased by 15% (P0.001) total mortality decreased by 11% (P0.001) Decreases were similar for all treatment modalities Cholesterol reduc
30、tion did not increase non-CHD mortality,Lp(a) in Atherogenesis: Another Culprit?,Identical to LDL particle except for addition of apo(a) Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all Accumulates in atherosclerotic plaque Binds apo B-contai
31、ning lipoproteins and proteoglycans Taken up by foam cell precursors May interfere with thrombolysis,Maher VMG et al. JAMA. 1995;274:1771-1774. Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176.,Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort,RR=relative risk
32、; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276:544-548.,1.9,1.8,1.8,1.2,2.7,3.6,RR,0.1,1,10,2,5,0.2,0.5,Lp(a) TC HDL-C HT GI Smoking,2004 PPS,Lp(a)=lipoprotein(a); CHD=coronary heart disease.,Adapted from Ariyo AA et al. N Engl J Med. 2003;349:2108-2115.,Lp(a): Vascular E
33、vents by Sex and Quintile at Baseline (Cardiovascular Health Study),AFCAPS/TexCAPS: RR of Acute Coronary EventsLDL-C and Homocysteine*,*Median LDL-C=149 mg/dL; median Hcy=11.27 mmol/L. Calculated on 5 patient-years at risk to prevent one event. RR=relative risk; Hcy=homocysteine; CI=confidence inter
34、val. Data from Ridker PM et al. Circulation. 2002;105:1776-1779.,RR with 95% CI,0.0 0.5 1.0 1.5,Lovastatin (L) better,Placebo (P) better,No. Needed to Treat 104 130 115 26,AFCAPS/TexCAPS: RR of Acute Coronary EventsTC:HDL-C Ratio and CRP Level*,*Median TC:HDL-C ratio=5.96; median CRP=0.16 mg/dL. Cal
35、culated on 5 patient-years at risk to prevent one event. RR=relative risk; CRP=C-reactive protein; CI=confidence interval. Adapted from Ridker PM et al. N Engl J Med. 2001;344:1959-1965.,RR with 95% CI,0.0 0.5 1.0 1.5 2.0 2.5,Lovastatin (L) better,Placebo (P) better,No. Needed to Treat 983 43 35 62,
36、TM, 2001, Professional Postgraduate Services,www.lipidhealth.org,LRC Follow-up Study: CVD Mortality by NonHDL-C and LDL-C in Men,LRC=Lipid Research Clinics; RR=relative risk; CI=confidence interval. Adapted from Cui Y et al. Arch Intern Med. 2001;161:1413-1419.,0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2
37、.00 2.25 2.50 2.75 3.00,RR with 95% CI,TM, 2001, Professional Postgraduate Services,www.lipidhealth.org,LRC Follow-up Study: CVD Mortality by NonHDL-C and LDL-C in Women,LRC=Lipid Research Clinics; RR=relative risk; CI=confidence interval. Adapted from Cui Y et al. Arch Intern Med. 2001;161:1413-141
38、9.,0 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00,RR with 95% CI,TM, 2001, Professional Postgraduate Services,www.lipidhealth.org,ACCESS: Change in LDL-C, NonHDL-C in All Patients at 54 Weeks,ACCESS=Atorvastatin Comparative Cholesterol Efficacy and Safety Study. Data from Ballantyne CM et al. Am J Cardio
39、l. 2001;88:265-269.,-42,-29,-36,-28,-36,-38,-26,-32,-26,-32,-50,-40,-30,-20,-10,0,10,20,LDL-C,NonHDL-C,% D,Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin (n=1,888) (n=474) (n=472) (n=461) (n=462),TM, 2001, Professional Postgraduate Services,www.lipidhealth.org,Age-Adjusted Total Cholest
40、erol Levels in NHANES III vs NHANES 1999-2000,Ford ES et al. Circulation. 2003;107:2185-2189.,NHANES=National Health and Nutrition Examination Survey,Elevated TC Effects on Risk of CHD Death in Younger Men: A Meta-analysis,*The difference in absolute risk with high baseline TC vs risk with favorable
41、 levels (200 mg/dL). As compared with men with TC 160 mg/dL. MRFIT=Multiple Risk Factor Intervention Trial; CHA=Chicago Heart Association Detection Project in Industry; PG=Peoples Gas Company.Stamler J, et al. JAMA. 2000;19:311-318.,MRFIT CHA PG (37-53 y) (30-55 y) (32-66 y) Absolute risk 15.5 54.2
42、154.0 (per 1,000) TC 240 mg/dL Absolute excess risk* 12.1 43.6 81.4 (per 1,000) TC 240 mg/dL Relative risk 8.09 11.93 8.06 TC 280 mg/dL,LDL-C target levels (mg/dL) 2 RF: 130 CHD: 100National Center for Health Statistics. National Health and Nutrition Examination Survey (III); 1994. (Data collected 1
43、991-1994.) Pearson TA et al. Arch Intern Med. 2000;160:459-467.,% not atLDL-C targets,2 RF CHD Risk profile,63,82,82.5,54.6,0,20,40,60,80,100,NHANES III,L-TAP,Adult Population Not Reaching LDL-C Targets,18,9.9,13,14.4,11.2,9.4,7.9,16.6,0,5,10,15,20,25,% of patients,100 101- 111- 121- 131- 141- 151-
44、160110 120 130 140 150 160,LDL-C (mg/dL) on-treatment,n = 1,460,L-TAP: Majority of Patients With CHD Do Not Reach NCEP LDL-C Targets,Pearson TA et al. Arch Intern Med. 2000;160:459-467. Other L-TAP data courtesy of TA Pearson.,% of patients,L-TAP: Majority of High-Risk Patients Without CHD Do Not Re
45、ach NCEP LDL-C Targets,Pearson TA et al. Arch Intern Med. 2000;160:459-467. Other L-TAP data courtesy of TA Pearson.,n = 2,285,130,130- 140,141- 150,151- 160,161- 170,171- 180,181- 190,191- 200,200,LDL-C (mg/dL) on-treatment,L-TAP: Patient Success in Achieving Target LDL-C Levels,Pearson TA et al. A
46、rch Intern Med. 2000;160:459-467.,Nondrug therapy,282,361,108,751,861,1,924,1,352,4,137,Drug therapy,No.,% patient success,Low risk (P=0.001),High risk (P0.001),CHD (P=0.004),All patients,Note: P values based on univariate analysis comparing success rates among patients who did, and patients who did
47、 not, receive lipid-lowering therapy.,ATP III: New Features of Guidelines Updated Lipid/Lipoprotein Classifications,Optimal LDL-C level: identified as 100 mg/dL Categorical low HDL-C: raised to 40 mg/dL to more accurately define patients at increased risk TG classification cutpoints: lowered to focus more attention on moderate elevations normal: 150 mg/dL borderline high: 150199 mg/dL high: 200499 mg/dL very high: 500 mg/dL,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.,
