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1、Mixed Dyslipidemia Attenuating risk- treatment beyond LDL.,PLA General Hospital YAN Muyang,Residual Cardiovascular Risk in Major Statin Trials,4 HPS Collaborative Group. Lancet. 2002;360:7-22. 5 Shepherd J, et al. N Engl J Med. 1995;333:1301-1307 6 Downs JR, et al. JAMA. 1998;279:1615-1622.,1 4S Gro
2、up. Lancet. 1994;344:1383-1389. 2 LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3 Sacks FM, et al. N Engl J Med. 1996;335:1001-1009., LDL-C,N,4444,4159,20 536,6595,6605,9014,-35%,-28%,-29%,-26%,-25%,-25%,Secondary,High Risk,Primary,Patients Experiencing Major CHD Events, %,4S1,LIPID2,CARE3,HP
3、S4,WOSCOPS5,AFCAPS/ TexCAPS6,19.4,12.3,10.2,8.7,5.5,6.8,28.0,15.9,13.2,11.8,7.9,10.9,CHD events occur in patients treated with statins,HDL-C* (mg/dL),Major CVD Events, %,Patients With LDL-C 80 mg/dL on Atorvastatin 80 mg,n = 4874 *On-treatment level (3 months),Barter P, et al. Poster ACC. 2006. Abst
4、ract 914-203.,40,41-50,51-60,60,P 0.0001 for Inverse Relationship,Treating to New Targets (TNT) Study,Low HDL-C Increases CVD Risk Even if LDL-C Levels Are Well-Controlled,PathophysiologyPatients with high triglycerides:Increase in VLDL remnantsIncrease in IDLSmall, dense LDLLp-PLA2 and Apo-CIII - p
5、ro-atherogenicEven on statins these patients have increased riskWhat is optimum TG level?Guidelines : 150In patients with coronary disease, worsening disease, recurrent symptoms, 100 may be optimal.TG/HDL Ratio = 3.5,Lp-PLA2: lipoprotein-associated phospholipase A2 APO-CIII: Apolipoprotein CIII,Beyo
6、nd LDL as a TargetAddressed in guidelines as concept of “non-HDL-cholesterol“Not a new concept: Helsinki Heart Study of 1987 entry criteria was high levels of non-HDL-C 1Target non-HDL 100 (but not routinely on lab request slip)ADA Expert Panel: Patients with type 2 diabetes and other risk factors s
7、hould also have non-HDL 100; apoB goal 90 mg/dl, LDL particle number 1000 2,1. Frick et al. N Engl J Med. 1987;317:1237-1245. 2. Brunzell et al. Diabetes Care 31: 811-822,NonHDL-C Superior to LDL-C in Predicting CHD Risk,Liu J, et al. Am J Cardiol. 2006;98:1363-1368.,NonHDL-C, mg/dL,Relative CHD Ris
8、k,LDL-C, mg/dL,Within non-HDL-C levels, no association was found between LDL-C and the risk for CHD. In contrast, a strong positive and graded association between nonHDL-C and risk for CHD occurred within every level of LDL-C NonHDL-C is a stronger predictor of CHD risk than LDL-C,Residual CVD Risk
9、in Patients Treated With Intensive Statin Therapy,Standard statin therapy,Intensive high-dose statin therapy,PROVE IT-TIMI 221,IDEAL2,TNT3,N,LDL-C,* mg/dL,1 Cannon CP, et al. N Engl J Med. 2004;350:1495-1504. 2 Pedersen TR, et al. JAMA. 2005;294:2437-2445. 3 LaRosa JC, et al. N Engl J Med. 2005;352:
10、1425-1435.,4162,8888,10 001,95,*Mean or median LDL-C after treatment,62,104,81,101,77,26.3,13.7,10.9,12.0,22.4,8.7,Patients Experiencing Major CVD Events, %,Statin/ Fibrate Combination Therapy: Pharmacokinetic Interactions,Backman JT, et al. Clin Pharmacol Ther. 2002;72:685-691. Abbott Laboratories.
11、 Data on file; 2005. Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. Prueksaritanont T, et al. Drug Metab Dispos. 2002;30:1280-1287. Martin PD, et al. Clin Ther. 2003;25:459-471. Bergman AJ, et al. J Clin Pharmacol. 2004;44:1054-1062.,Backman JT, et al. Clin Pharmacol Ther. 2005;78:154-67. TriCor
12、 PI. Abbott Laboratories;2004. Kyrklund C, et al. Clin Pharmacol Ther. 2001;69:340-345. Pan W-J, et al. J Clin Pharmacol. 2000;40:316-323. Backman JT, et al. Clin Pharmacol Ther. 2000;68:122-129.,New agent : ABT-335 is being studies in combination with simvastatin and with atorvastatin. Study result
13、s at ACC 08 - good efficacy and safety in lowering TG and raising HDL Good safety data for extended-release niacin plus statins but some adherence/dose titration issues In patients with high/very high TG, and poorly controlled diabetes, fenofibrate or fenofibrate plus omega-3 fatty acids may be bett
14、er choice Other benefits of fenofibrate on small vessels disease SEACOAST data: niacin raises HDL independent of TG level Fenofibrate requires TG to be high to raise HDL Generally, men tolerate niacin better than women,AIM HIGH: Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High T
15、riglycerides and Impact on Global Health Outcomes 1 ER niacin plus simvastatin vs simvastatin alone at comparable levels of on-treatment LDL-C n = 3,300 Completion Q3, 2010:No difference,stop before the time.HPS2-THRIVE: A Randomized Trial of the Long-Term Clinical Effects of Raising HDL Cholesterol
16、 With Extended Release Niacin/Laropiprant 2Participants have established CVD and receive LDL lowering therapy (40 mg of simvastatin or 10/40 mg ezetimibe/simvastatin) Laropiprant - selective prostaglandin D2 receptor-1 (DP1) antagonist -reduces frequency and intensity of niacin-induced flushingn = 2
17、0,000Completion Q4, 2011,1. http:/clinicaltrials.gov/ct/show/NCT00120289 2. http:/www.controlled- Action to Control Cardiovascular Risk in DiabetesClinical benefit of adding fenofibrate to patients receiving simvastatin therapyn = 5,900 Completion Q3, 2009FIRST: The effects of Fenofibrate on cIMT in
18、 patients with Residual risk on Statin Therapy 1Safety and efficacy study of ABT-335 in combination with atorvastatin Uses carotid intima media thickness as surrogate end pointRecruitingARBITER-2: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2ER niacin added to lipid-lowering therapy in patients with known CHD and low HDL-C levels Mean CIMT increased significantly in those not treated with niacin, while no significant increase in CIMT was found in the niacin-treated patients.,
