血脂管理(2010年).ppt

1、Robert H. Eckel, M.D. Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Division of Cardiology Professor of Physiology and Biophysics Charles A. Boettcher II Chair in Atherosclerosis University of Colorado Denver School of Medicine Director Lipid Clinic, University Hospital,“L

2、ipidology (Pre ATP-IV): Everything I Can Discuss on What You Should Know” How to Prevent a Heart Attack June 12, 2010,The Lipid Patient Five Groups, LDL cholesterol TG ( HDL cholesterol LDL cholesterol + TG HDL cholesterol Lipoprotein (a),Assessing Acquired Causes of Dyslipidemia,Lifestyle Diet, ina

3、ctivity, alcohol, tobacco Medications Steroids, diuretics, -blockers, PIs, cis-RA Insulin resistance Thyroid disease Liver disease Kidney disease Proteinuria GFR,Revised NCEP ATP III LDL-C Goals,Circulation 110:227, 2004,* Consider drug options if below goal, but above goal for next higher risk leve

4、l,Revised NCEP ATP III Non-HDL Goals,Circulation 110:227, 2004,* Consider drug options if below goal, but above goal for next higher risk level,NHLBI Clinical Guidelines for CVD Risk Reduction: Organizational Structure,Major Lipids, Apolipoproteins and CVD Risk: The Emerging Risk Factors Collaborati

5、on,302,430 people without CVD from 68 long-term prospective studies Mostly Europe and North America 2.79 million person-years of follow-up 8857 non-fatal MIs 3928 CHD deaths 2534 ischemic strokes 513 hemorrhagic strokes 2536 unclassified strokes,ERF Collaboration, JAMA 302:1993, 2009,CHD Risk: Non-H

6、DL vs. HDL Cholesterol,ERF Collaboration, JAMA 302:1993, 2009,(n = 302,430),Apolipoprotein B,One apo B molecule/particle Assesses potentially atherogenic particle number Helps to distinguish risk of CHD in patients with hypertriglyceridemia Highly correlated with non-HDL cholesterol 0.95 when TG 300

7、 mg/dl 0.80 when TG higher,Apo B May Predict Vascular Events Better than LDL Cholesterol,Observational studies Quebec Cardiovascular Study LIPID (placebo) AMORIS Interventional studies AFCAPS/TexCAPS (lovastatin) LIPID (pravastatin) IDEAL (simvastatin, atorvastatin) TNT (atorvastatin),CHD Risk Based

8、 on Lipids and Apolipoproteins,ERF Collaboration, JAMA 302:1993, 2009,(n = 91,307),The real value of apo B is in patients without increases in LDL cholesterol, in patients with hypertriglyceridemia,0.0,0.5,1.0,1.5,2.0,2.5,3.0,50,100,150,200,250,300,350,400,Men,Women,RR,TG (mg/dL),Castelli WP. Can J

9、Cardiol. 4:5A, 1988,Impact of TG Levels on Relative Risk of CHD: Framingham Heart Study,Hypertriglyceridemia (1 mM ) and CHD: A Meta-Analysis (21 studies),MEN (65,863):1.30 (1.25-1.35) WOMEN (11,089):1.69 (1.45-1.97) Adjusted for HDL cholesterol (9 studies): MEN (29,105):1.17 (1.10-1.26) WOMEN (6,34

10、5):1.37 (1.13-1.66),Abdul-Maksoud M and Hokanson J.E., J Vasc Med, 2001,Relative Risk,Sarwar, N. et al. Circulation 2007;115:450-458,Risk of CHD in the Top vs. Bottom Tertile of Usual Log-TG by Study Characteristics,Sarwar N et al, Circulation 115:450, 2007,Thompson A and Danesh J, Journal of Intern

11、al Medicine, 259:481, 2006,Apo B and CHD Risk: MetaAnalysis,CHD and Ischemic CVA Risk: Emerging Risk Factors Collaboration Meta-Analysis,(n = 302,430 people),ERF Collaboration, JAMA 302:1993, 2009,CHD,CVA,Normal,IIA,IIB,IV,Nl TG, TG, HDL,Lamarche B et al, Am J Card 75:1189, 1995,1.0,(0.001) 2.8,1.7,

12、1.0,(0.005) 2.7,(0.001) 3.1,(0.01) 2.1,OR,Odds are adjusted for age, smoking, alcohol, blood pressure, gender, and medications,HyperapoB,Odds Ratios for the Development of CHD: Lipid and Lipoprotein Phenotypes,Management of Triglycerides,Goal: Is it TG? No, its non-HDL cholesterol! Then isnt it TG 1

13、50 mg/dl? Or should it be apo B?,Correlations Between Apo B, Cholesterol, LDL Cholesterol and Non-HDL Cholesterol,Sniderman AS et al, Am J. Card 91:1173, 2003,ACC/ADA Lipid Goals,Brunzell JD et al, JACC 51:1512, 2008,LDL-C (mg/dL),35,30,25,20,15,10,5,0,0,25,50,75,100,125,150,175,200,Event Rate (%),4

14、S P,4S Tx,LIPID P,HPS P,LIPID Tx,HPS Tx,CARE P,TNT 10 mg,TNT 80 mg,LDL-C Reduction in Statin Trials,Charland SL, et al. Circulation 2005; 112:II-816,CARE Tx,Statins: The Down Side,Abnormal AST and ALT 3X ULN: 50 fold in CK + renal impairment 0.1%,Bruckert E et al, Cardiov Drugs 19:403, 2005 Brown WV

15、, Curr Opin Lipid 19:558, 2008 Onusko E, J Fam Pract 57:449, 2008,What the Clinician Needs to Consider,Hypothyroidism Other drugs Fibrates, azole anti-fungals, cyclosporine, macrolides, diltiazem, HIV protease inhibitors Genetic differences in drug-metabolizing enzymes, e.g. OATP1B1 SLCO1B1, CYP2D2,

16、 3A4 Neuromuscular diseases Mitochondrial myopathy, McArdles disease, myotonic dystrophy, polymyositis,Asymptomatic,CK in high risk patients only,CK measured: 5 x normal,Mildly Symptomatic,Symptoms worse: repeat CK 104:e9051; Schwartz GG et al. JAMA. 285:1711, 2001,Where are we at on ezetimibe?,ARBI

17、TER 6-HALTS,“HALTS”: HDL And LDL Treatment Strategies Purpose Compare the effectiveness of combination lipid lowering therapy with either extended-release niacin or ezetimibe added to long-term statin therapy for the endpoint of carotid intima-media thickness over 14 months PROBE Design Prospective,

18、 randomized, parallel-group, open-label study involving blinded evaluation of endpoints Walter Reed Army Medical Center- Washington, D.C. Washington Adventist Hospital- Takoma Park, MD,Overall Baseline Characteristics,N = 208 80% male Age: 65 11 years All on statins 42 25 mg/d 6 5 years duration 95%

19、 simvastatin or atorvastatin,Baseline measured variables TC 147 26 mg/dL LDL-C 82 23 mg/dL HDL-C 42 8.5 mg/dL TG134 68 mg/dL CIMT Mean0.8977 0.1583 mm Max1.0179 0.1653 mm,Baseline characteristics balanced in the 2 treatment groups. Baseline statin dose: Little room for additional statin titration.,R

20、esults: Lipid Concentrations,Niacin: HDL increased by 18.4% to 50 mg per deciliter LDL and TG Ezetimibe: LDL decreased by 19.2%, to 66 mg per deciliter,Results: Primary Endpoint Between-group Change in CIMT,Niacin was superior to ezetimibe for the primary endpoint of the between group difference in

21、carotid intima-media thickness. P = 0.003,Results: LDL Change vs. CIMT Change,In a post hoc analysis, we explored the bivariate relationships between changes in LDL cholesterol levels and mean carotid intimamedia thickness.,Ezetimibe R = -0.31; P 0.001,Niacin R = -0.01; P = 0.92,Paradoxical increase

22、 in CIMT in patients treated with ezetimibe with greater reductions in LDL cholesterol. This effect was not observed with niacin. Hypothesis generating regarding the net effects of ezetimibes complex mechanism of action in patients with dyslipidemia.,Posted online at ,Major adverse cardi

23、ovascular events occurred at a significantly lower incidence in the niacin (2/160 patients 1.2% vs. the ezetimibe group (9/165 patients 5.5%) Chi-square p=0.04; Log-rank p = 0.047,Results: Major CVD Events,HDL: So what do we really know?,HDL and Atherosclerosis,Anti-oxidant Anti-inflammatory Anti-th

24、rombotic prostacyclin Promotes vascular reactivity NOS Reverse cholesterol transport,The HDL Proteome,Vaisar T et al. J Clin Invest. 117:746, 2007,HDL- Paradox,CETP deficient Japanese families with HDL levels 80-100 mg/dL or higher in heterozygotes But, possibly an increase in CHD risk Apo A1Milano

25、Low HDL octagenarians with low CHD risk Tangier Disease ABCA1 gene deficiency Genetically low HDL: Turkey (HTGL gene mutation) and China When relocated to an urban environment, CHD risk Many patients without low HDL have CHD Pro-inflammatory HDL? Type 1 diabetes,Novel Therapies for Raising HDL,Recon

26、stituted HDL Apo A-1 Apo A-1 Milano Apo A-1 peptides PPAR-/ dual agonists New drug classes,For HDL, wheres the evidence?,Coronary Drug Project15-Year Mortality Results,Niacin,n=1,119,Placebo,n=2,789,Risk,Reduction,P,Total Mortality,52%,58%,-11%,0.005,FBG 100 mg/dL,48%,53%,-9%,0.05,FBG 100 mg/dL,56%,

27、63%,-12%,0.005,CHD Mortality,36%,41%,-12%,0.01,Canner PL et al, J Am Coll Cardiol. 8:1245, 1986.,CDP - METABOLIC SYNDROME,69% ,28% ,Canner PL et al, Am J Cardiol. 2006 97:477, 2006,n = 124,CDP - METABOLIC SYNDROME,27% ,17% ,n = 368,Canner PL et al, Am J Cardiol. 2006 97:477, 2006,Niacin and CVD Even

28、ts in the Metabolic Syndrome: FATS, HATS, AFREGS,Zhao XQ et al, Am J Cardiol. 104:1457, 2009,Definitive HDL Cholesterol Outcome Studies,HPS2-Thrive This study is currently recruiting participants. Verified by University of Oxford, November 2009 First Received: April 17, 2007 Last Updated: November 4

29、, 2009 History of Changes Purpose - The primary aim is to assess the effects of raising HDL cholesterol with extended release niacin/laropiprant vs. matching placebo on the risk of MI or coronary death, stroke, or the need for revascularization in people with a history of circulatory problems.,Defin

30、itive HDL Cholesterol Outcome Studies,Aim High Plaque Inflammation and Dysfunctional HDL Cholesterol in Participants Receiving Niacin and Statins in the AIM-HIGH Study (The HDL Proteomics Study) This study is currently recruiting participants. Verified and funded by National Heart, Lung, and Blood I

31、nstitute (NHLBI), April 2009 First Received: April 10, 2009 No Changes Posted Purpose: This study will examine MRI images and blood samples of participants who are taking niacin plus statins or statins alone to determine the effect of these medications on inflammation in atherosclerotic plaques.,IMPROVE-IT,IMPROVE-IT: Examining Out