1、HDL as a Therapeutic Target Daniel J. Rader, M.D.,100,160,220,Risk of CHD,Low HDL-C is an Independent Predictor of CHD Risk Even When LDL-C is Low,HDL-C (mg/dL),LDL-C (mg/dL),25,Gordon T et al. Am J Med 1977;62:707-714.,45,65,85,ATP III: New Definition of Low HDL-C,Expert Panel on Detection, Evaluat
2、ion, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,Low HDL-C was redefined as 40 mg/dL,ATP III: The Metabolic Syndrome,Diagnosis is established when 3 of these risk factors are present.,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Ad
3、ults. JAMA 2001;285:2486-2497.,Is HDL-C Simply a Marker of Increased Cardiovascular Risk?,Smoke Are sedentary Are obese Are insulin resistant or diabetic Have hypertriglyceridemia Have chronic inflammatory disorders,Low HDL-C levels are commonly found in patients who:,Production of Apo A-I by Liver
4、and Intestine,A-I,A-II,Liver,Intestine,HDL,A-I,HDL,Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits Regression of pre-existing atherosclerosis in animals,Increased Apo A-I Production is Antiatherogenic in Animals,Increase apo A-I production Promote reverse cholest
5、erol transport Delay catabolism of HDL,HDL Metabolism as a Therapeutic Target: Potential Strategies,Small molecule upregulation of apo A-I gene transcription Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano) Administration of peptides based on apo A-I sequence Somatic ge
6、ne transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells),Approaches to Increasing Apo A-I Production,Increase apo A-I production Promote reverse cholesterol transport Delay catabolism of HDL,HDL as a Therapeutic Target: Potential Strategies,HDL and Reverse Cholesterol Transport,Live
7、r,CE,CE,FC,LCAT,FC,Bile,SR-BI,ABCA1,Macrophage,Mature HDL,Nascent HDL,FC,Regulation of Cholesterol Efflux in the Macrophage,FC,FC,oxysterols,LXR/RXR,ABCA1,PPARs,Pharmacologic Manipulation of Cholesterol Efflux,LXR/RXR,PPARs,Fibrates, TZDs, new agents,New agents,FC,ABCA1,Increase apo A-I production P
8、romote reverse cholesterol transport Delay catabolism of HDL,HDL as a Therapeutic Target: Potential Strategies,Antioxidant effects Inhibition of adhesion molecule expression Inhibition of platelet activation Prostacyclin stabilization Promotion of NO production,Mechanisms Other Than Reverse Choleste
9、rol Transport by Which HDL May be Antiatherogenic,Liver,CE,CE,FC,FC,LCAT,FC,Bile,SR-BI,ABCA1,Macrophage,A-I,TG,CE,HDL Metabolism: Intravascular Remodeling of HDL,Kidney,PL,FC,PL,Liver,HL,A-I,TG,CE,HDL Metabolism: Role of Hepatic Lipase,Kidney,PL,HDL2,Liver,CE,CE,FC,FC,LCAT,FC,Bile,SR-BI,ABCA1,Macrop
10、hage,HDL Metabolism: Role of CETP,FC,Kidney,LDLR,CE TG,CETP,B,VLDL/LDL,HDL Metabolism in CETP Deficiency,CE,FC,FC,LCAT,ABCA1,Macrophage,A-I,CE,FC,CE TG,CETP,B,VLDL/LDL,Delayed catabolism,X,Okamoto H et al. Nature 2000;406:203-207.,Inhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits Significantl
11、y Reduced Aortic Atherosclerosis,% Aortic Lesion,Control,Simvastatin,JTT-705,HDL Metabolism: Influence of CETP Inhibition,Liver,CE,CE,FC,FC,LCAT,FC,Bile,SR-BI,ABCA1,Macrophage,FC,LDLR,CE TG,CETP,B,VLDL/LDL,X,Weight reduction and increased physical activity LDL-C is primary target of therapy Non-HDL-
12、C is secondary target of therapy (if triglycerides 200 mg/dL) Consider nicotinic acid or fibrates,Management of Low HDL-C,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,Therapeutic lifestyle changes Smoking cessation Regular aerobic
13、 exercise Weight loss Alcohol use?,Management of Low HDL-C,Therapeutic lifestyle changes Pharmacologic therapy Statins,Management of Low HDL-C,Patients with Events (%),Scandinavian Simvastatin Survival Study Group. Lancet 1995;345:1274-1275.,4S: Major Coronary Events by HDL-C Subgroup,HDL-C (mg/dL),
14、Placebo,Simvastatin,38,3944,4552,53,RR=0.67,RR=0.71,RR=0.57,RR=0.70,Patients with Events (%),LIPID Study Group. N Engl J Med 1998;339:1349-1357.,LIPID: CHD Events by HDL-C Subgroups,HDL-C,Placebo,Pravastatin,39 mg/dL,39 mg/dL,25%,24%,Patients with Events (%),Sacks FM et al. N Engl J Med 1996;335:100
15、1-1009.,CARE: CHD Events by HDL-C Subgroups,HDL-C,Placebo,Pravastatin,37 mg/dL,37 mg/dL,P = 0.008,P 0.001,Events (%),Downs JR et al. JAMA 1998;279:1615-1622.,AFCAPS/TexCAPS: Risk Reduction by HDL-C Tertile at Baseline,HDL-C Levels,Placebo,Lovastatin,34 mg/dl,3539 mg/dl,40 mg/dl,71,40,68,41,44,35,44%
16、 RR,40% RR,20% RR,Therapeutic lifestyle changes Pharmacologic therapy Statins Fibrates,Management of Low HDL-C,VA-HIT: Major Coronary Events in Gemfibrozil vs. Placebo Groups,Cumulative Incidence (%),0,Rubins HB et al. N Engl J Med 1999;341:410-418. Copyright 1999, Massachusetts Medical Society. All
17、 rights reserved.,1,2,3,4,5,6,Year,Placebo,Gemfibrozil,22% reduction P = 0.006,VA-HIT: Lipid Concentrations According to Year of Study and Treatment Group,TC (mg/dL),Year,LDL-C (mg/dL),Year,HDL-C (mg/dL),Year,TG (mg/dL),Year,Placebo,Gemfibrozil,4%, P0.001,No change,Gemfibrozil & Placebo,Placebo,Gemf
18、ibrozil,+6%, P0.001,Placebo,Gemfibrozil,31%, P0.001,Rubins HB et al. N Engl J Med 1999;341:410-418. Copyright 1999, Massachusetts Medical Society. All rights reserved.,VA-HIT: Changes in Plasma Lipids during Treatment as Predictors of Coronary Events,Robins SJ et al. JAMA 2001;285:1585-1591. Copyrig
19、ht 2001, American Medical Association.,Therapeutic lifestyle changes Pharmacologic therapy Statins Fibrates Niacin,Management of Low HDL-C,Efficacy of Extended-Release Niacin,Change from Baseline,2500 mg,3000 mg,Goldberg A et al. Am J Cardiol 2000;85:1100-1105.,2000 mg,1500 mg,1000 mg,500mg,HDL-C,LD
20、L-C,Lp(a),TG,9%,14%,22%,21%,17%,29.5%,30%,26%,22%,15%,10%,28%,35%,44%,39%,11%,5%,26%,3%,12%,30%,24%,17%,Lifestyle changes and secondary causes Pharmacologic therapy If LDL-C elevated: statin If TG elevated: fibrate If isolated low HDL-C: niacin Combination therapy,Management of Low HDL-C,Change (%),
21、Wolfe ML et al. Am J Cardiol 2001;87:476-479. Copyright 2001, Excerpta Medica Inc. Reprinted with permission.,Addition of Extended-Release Niacin to a Statin because of Persistently Low HDL-C,TC,LDL-C,HDL-C,TG,CV Events,Event Rate (%),Brown BG et al. Circulation 1998;98:I-635.,Familial Atheroscleros
22、is Treatment Study (FATS): 10-Year Follow-up Results,Usual Care (n=101),Deaths,LDL-C 188166 mg/dL; HDL-C 3840 mg/dL ; TG 208220 mg/dL,LDL-C 202106 mg/dL; HDL-C 4353 mg/dL; TG 210134 mg/dL,Triple Therapy (n=75),19.8,18.8,1.3*,* p0.05,5.3*,LDL-C remains the primary target of lipid-altering therapies H
23、DL-C is an important CHD risk factor Even small increases in HDL-C may confer substantial benefit Intervention to raise HDL-C levels should be considered in high-risk patients,Summary,48-year-old man with metabolic syndrome and CHD After therapeutic lifestyle changes and a starting dose of statin:Cholesterol 179 mg/dLTriglycerides 252 mg/dLLDL-C 97 mg/dL HDL-C 32 mg/dLGlucose 104 mg/dL,Approach to the Patient with Low HDL-C,
