1、ATP III: Management of Diabetic Dyslipidemia,Primary target of therapy: identification of LDL-C; goal for persons with diabetes: 100 mg/dL Therapeutic options: LDL-C 100129 mg/dL: increase intensity of TLC; add drug to modify atherogenic dyslipidemia (fibrate or nicotinic acid); intensify risk facto
2、r control LDL-C 130 mg/dL: simultaneously initiate TLC and LDL-Clowering drugs TG 200 mg/dL: nonHDL-C* becomes secondary target,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.,Note: Diabetic dyslipidemia is essentially atherogenic d
3、yslipidemia in persons with type 2 diabetes. *NonHDL-C goal is set at 30 mg/dL higher than LDL-C goal., 2001, Professional Postgraduate Services,www.lipidhealth.org,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 diabe
4、tes(n=782) (n=8,232),LIPID Study Group. N Engl J Med. 1998;339:1349-1357.,%,Baseline Aggressive Rx Moderate Rx P Characteristic (N=1360) (N=1318) Value,Campeau et al. Circulation. 1999;99:3241-3247.,Post-CABG: Aggressive LDL-C Lowering Delays Progression of Atherosclerosis in Women, Elderly, and Pat
5、ients With Selected CHD Risk Factors,n % n %,Age (y): 60 479 30 513 40 0.003 60 881 27 805 39 0.0001 Female 88 15 63 24 0.25 Male 1272 29 1255 40 0.0001 Current smoker: Yes 137 32 139 50 0.01 No 1223 27 1179 38 0.0001 Hypertension: Yes 655 27 608 39 0.0002 No 705 28 710 39 0.0003 Diabetes mellitus:
6、Yes 122 27 104 43 0.04 No 1238 28 1214 39 0.0001,n=number of grafts.,Grafts With Substantial Progression,0,2,4,6,Mean annual CHD mortality rate/1,000,Adapted from Fontbonne A et al. Diabetologia. 1989;32:300-304.,Cholesterol (mg/dL),220,220,220,220,TG 123 mg/dL TG 123 mg/dL,Fasting TG and Risk for C
7、HD Death: Paris Prospective Study,0,1,2,3,CHD mortality (per 1,000),Fontbonne AM et al. Diabetes Care. 1991;14:461-469.,29 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,% Macro
8、vascular 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,% 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
9、Metab Res. 1985;15(suppl):15-19.,Prevalence of Macrovascular Disease and CHD According to Quintiles of Fasting C-Peptide,Finnish 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
10、 age: 55 years mean duration: 3.2 years intervention group: individualized counseling reducing weight, total intake of fat 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 in
11、dex. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.,Finnish Diabetes Prevention Study: Success in Achieving Treatment 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
12、 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,(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 Crit
13、eria 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 Intervention standard lifestyle recommendations + placebo twice daily standard lifestyle recommendations + metformin titrated to 850 mg twice daily intensive lifestyle modifica
14、tion (low-calorie/low-fat diet, moderate physical activity 150 min/wk) troglitazone (later withdrawn) Outcome type 2 diabetes over average follow-up of 2.8 years,Progression to Atherosclerotic Clinical Events in Patients With Diabetes,AGE=advanced glycation end products; CRP=C-reactive protein; HDL=
15、high-density lipoprotein; HTN=hypertension; IL-6=interleukin-6; LDL=low-density lipoprotein; PAI-1=plasminogen activator inhibitor-1; SAA=serum amyloid A protein; TF=tissue factor; TG=triglycerides; tPA=tissue-type plasminogen activator Biondi-Zoccai GGL et al. J Am Coll Cardiol. 2003;41:1071-1077.,
16、Subclinical Atherosclerosis,Atherosclerotic Clinical Events,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
17、 on Step I diet Randomized, 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.,mg/dL,* Significant difference betwe
18、en genders. Steiner G et al. Am J Cardiol. 1999;84:1004-1010.,DAIS: Mean Baseline Lipoprotein Levels,P=0.0005*,P=0.0001*,P=NS,P=NS,Mean % D,*P=0.0001. Steiner G. Diabetes. 1999;48(suppl 1):A2. Abstract 0005.,DAIS: Interim Lipid Results in Patients With Type 2 Diabetes,*Researchers report that result
19、s suggest benefit to patients. Steiner G. XIIth International Symposium on Atherosclerosis; June 27, 2000; Stockholm, Sweden.,DAIS: Final Results in Patients With Type 2 Diabetes,CAD Treatment with fenofibrate resulted in 40% reduction in rate of progression of localized CAD versus placebo 23% reduc
20、tion in combined coronary events following fenofibrate treatment (P=NS*) Lipids Average reductions with fenofibrate: TC, 10%; LDL-C, 6%; TG, 29%; average increase in HDL-C, 6% Safety Very few serious adverse events; no significant differences in tolerability between fenofibrate and placebo treatment
21、s; 95% compliance,Garber AJ. Clin Cornerstone. 2003;5:22-37. Garber AJ. Med 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 ty
22、pe 2 diabetes 50% of patients with newly diagnosed type 2 diabetes have CHD 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
23、 cerebrovascular disease,Framingham Heart Study 30-Year Follow-Up: CVD Events 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
24、 *P0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. 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 c
25、ardioprotective effect of being premenopausal risk of recurrent MI in diabetic 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=3,9
26、46),Type 2 on placebo (n=76),Type 2 on gemfibrozil (n=59),5-Yr incidence of 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,Insulin Resi
27、stance and Atherosclerosis: Posited Relationships,14,9,26,11,12,13,9,21*,34*,19*,0,10,20,30,40,50,Men without diabetes,Men with diabetes,TC 260,TG 235,VLDL-C 40,LDL-C 190,HDL-C 31,Prevalence (%),*P0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).A
28、dapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169.,Abnormal Lipid Levels in Men With Type 2 Diabetes,21,8,31,16,10,24,38,15,25*,17*,0,10,20,30,40,50,Women without diabetes,Women with diabetes,TC 275,TG 200,VLDL-C 35,LDL-C 190,HDL-C 41,Prevalence (%),*P0.05. LRC approximate 90th percentil
29、e age- and sex-matched values, except for HDL-C (10th percentile).Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169.,Abnormal Lipid Levels in Women With Type 2 Diabetes,Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502. Lamarche B et al. Circulation. 1997;95:69-75.,Significance
30、of Small, Dense LDL,Low cholesterol content of LDL particles particle number for given LDL-C level Associated with levels of TG and LDL-C, and levels of HDL2 Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B) Possible mechanisms of atherogenicity greate
31、r arterial uptake uptake by macrophages oxidation susceptibility,SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.,Potential Mechanisms of Atherogenesis in Diabetes,Abnormalities in apoprotein and lipoprotein particle distribution Glycosylation and advanced glyca
32、tion of proteins in plasma and arterial wall “Glycoxidation” and oxidation Procoagulant state Insulin resistance and hyperinsulinemia Hormone-, growth-factor, and cytokine-enhanced SMC proliferation and foam cell formation,ADA: Glycemic Control, BP, and Lipid Targets in Type 2 Diabetes,*Referenced t
33、o a nondiabetic range of 4.0%6.0% using a DCCT-based assay. ATP III guidelines suggest when TG is 200 mg/dL, use nonHDL-C (TC minus HDL-C); goal in patients with diabetes is 130 mg/dL (LDL-C goal + 30 mg/dL). For women, an HDL-C goal 10 mg/dL higher may be appropriate. DCCT = Diabetes Control and Co
34、mplications Trial,ADA. Diabetes Care. 2003;26(suppl 1):S33-S50.,ADA: Treatment Decisions by LDL-C Levels* in Adults With Type 2 Diabetes,Initiation LDL-C Initiation LDL-C Status level goal level goal With CHD, PVD, or CVD 100 100 100 100 Without CHD, PVD, and CVD 100 100 130 100,*Values represent mg
35、/dL. Some authorities recommend initiation of drug therapy between 100 and 129 mg/dL.CHD=coronary heart disease; PVD=peripheral vascular disease; CVD=cardiovascular disease,Medical nutrition tx Drug tx,ADA. Diabetes Care. 2003;26(suppl 1):S83-S86.,ADA: Order of Priorities for Treatment of Diabetic D
36、yslipidemia in Adults,LDL-C lowering first choice: HMG-CoA reductase inhibitors (statins) second choice: bile acid binding resin or fenofibrate HDL-C raising behavioral interventions (weight loss, physical activity, smoking cessation) difficult to achieve except with niacin, which should be used wit
37、h caution, or fibric acid derivative TG lowering* first priority: glycemic control fibric acid derivative (gemfibrozil, fenofibrate) statins (moderately effective at high dose in patients with TG and LDL-C),*Behavioral modification is also a first-line intervention.ADA. Diabetes Care. 2003;26(suppl
38、1):S83-S86.,ADA: Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults (contd),Combined hyperlipidemia first choice: improved glycemic control plus high-dose statin second choice: improved glycemic control plus statin* plus fibric acid derivative* (gemfibrozil or fenofibrate) third ch
39、oice: improved glycemic control plus resin plus fibric acid derivative orimproved glycemic control plus statin* plus niacin* (glycemic control must be monitored carefully),ADA. Diabetes Care. 2003;26(suppl 1):S83-S86.,*Combination of statins with niacin and especially with gemfibrozil or fenofibrate
40、 may carry an increased risk for muscle toxicity.,ADA: CHD Risk Stratification Based on Lipoprotein Levels* in Adults With Type 2 Diabetes,Risk LDL-C HDL-C TG High 130 40 400 Borderline 100-129 40-59 150-399 Low 100 60 150,*Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.,AD
41、A. Diabetes Care. 2003;26(suppl 1):S83-S86.,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,Nondiabetic 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=16
42、9),Survival (%),Year,Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI,Secondary 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 Re
43、duction in a Subgroup of Patients With Diabetes,Pyrl K et al. Diabetes Care. 1997;20:614-620.,Proportion alive,Yr since randomization,- 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 Patien
44、ts With Diabetes,Pyrl K et al. Diabetes Care. 1997;20:614-620.,Proportion without major CHD event,Yr since randomization,- P=0.002,- P=0.0001,Diabetic, simvastatin,Diabetic, placebo,Nondiabetic, simvastatin,Nondiabetic, placebo,32%,55%,WOSCOPS: Development of Type 2 Diabetes,Kaplan-Meier plots of ti
45、me to development of type 2 diabetes according to treatment assignment.Freeman DJ et al. Circulation. 2001;103:357-362.,% diabetic,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,First population-based study to evaluate nonHDL-C as predictor of CVD risk i
46、n patients with diabetes NonHDL-C: TC minus HDL-C (ie, all apolipoprotein B-containing atherogenic lipoproteins) VLDL, IDL, LDL, lipoprotein(a) May be useful marker of combined risk for all lipoprotein changes observed in diabetes ATP III recommends that nonHDL-C be used as secondary treatment targe
47、t in people with TG 200 mg/dL, especially with diabetes or the metabolic syndrome,Strong Heart Study: NonHDL-C as CVD Risk Predictor in Patients With Diabetes,Lu W et al. Diabetes Care. 2003;26:16-23.,Strong Heart Study: NonHDL-C Compared With Other CVD Risk Predictors,HR = hazard ratio. Data from L
48、u W et al. Diabetes Care. 2003;26:16-23.,TC:HDL-C ratio,TG,LDL-C,HDL-C,NonHDL-C,Lipoprotein,Decreased HR,Increased HR,Decreased HR,Increased HR,Steno-2: Effect of Therapies on Selected Risk Factors,Gaede P et al. N Engl J Med. 2003;348:383-393.,0,5,6,7,8,9,10,11,0,1,2,3,4,5,6,7,8,0,110,120,130,140,150,160,170,0,1,2,3,4,5,6,7,8,0,65,70,75,80,85,90,95,0,1,2,3,4,5,6,7,8,SBP (mm Hg),HbA1c (%),Follow-up (yr),Conventional therapy,Intensive therapy,
