Lipid is evolving Dyslipidemia Vascular disease Statin Beyond 관동의대제일병원 내과박정배
A Dyslipidemia 와혈관질환, 그연결고리는? &
약 80% 가 체내에서생성 약 20% 가 음식물에서흡수 Quantity of cholesterol in the body Bile acids 배설
동맥경화증의위험요인 흡연이고혈압의위험요인인것처럼, 혈액중에콜레스테롤의양이많으면심장질환과동맥경화의위험요인이된다. High blood cholesterol Obesity Hypertension Aging Smoking Diabetes mellitus Other Heredity Coronary Heart Disease
죽상경화증 (atherosclerosis) 과동맥경화증 (arteriosclerosis) Compliant Arterio and Atherosclerosis Systole Diastole Systole Diastole Constant Stroke Volume Aorta compliant stiffened Pulse pressure
Vascular event (MI or Stroke) rate and IMT O Leary DH et al. N Engl J Med.1999;340(1):14-22
Vascular event and Plaque Birgelen C et al. Circulation 2004;110:1579
Endothelial function test Vascular imaging Evolving of Dyslipid Vascular disease Pulse wave change (eg,augmentation index)
Markers of Atherosclerosis and arteriosclerosis are risk factors for adverse CV outcomes
8-year probability (per 1000) Risk of CHD by Multiple Risks & Cholesterol 60 60.2 50 40 34.6 30 23.2 20 10 3.9 0 Cholesterol mg/dl 185 335 185 335 185 335 185 335 (mmol/l) (4.8 8.7) (4.8 8.7) (4.8 8.7) (4.8 8.7) Glucose Intolerance 0 + + + Systolic BP (mmhg) 105 195 195 195 Cigarettes 0 0 + + LVH on ECG 0 0 0 + Kannel J. Am Coll Cardiol. 1990
Q & Dyslipidemia, 혈관질환과의연 A 결고리를어떻게끊을것인가? Dyslipidemia Vascular disease Statin & beyond
Benefit of Lowering Cholesterol Meta-analysis of 38 1 o & 2 o prevention trials, with 98,000 patients 0.0 Mortality log odds ratio 0.2 0.4 0.6 Mortality in CHD, p=0.012 Total mortality, p=0.04 0.8 1.0 0 4 8 12 16 20 24 28 32 Cholesterol reduction (%) Gould AL et al. Circulation 1998;97:946 952
2007 AHA ADA " 당뇨병환자심혈관질환예방 " 생활습관 적정한감량수치는기존체중의 5~7% 감량 음식 : 포화지방 7% 트랜스불포화지방산 1% 콜레스테롤 200mg/d / 전체칼로리 염분섭취량 : 1200~2300mg/ 일 운동 : 심혈관계질환예방 - 중등도 150 분 / 강력한운동 90 분 / 주체중감량및유지 : 중등도 / 강력한운동 7 시간 / 주 금연 : 금연권고 + 담배를끊고자하는의지평가필요. 생활습관개선요법이최대 3 개월까지
지혈이상증의치료 약물투여 식이요법 운동 고지혈증치료의기본원칙 1) 고지혈증의종류에따라식이요법과운동처방을약 3 개월동안시행한다. 2) 식이요법과운동요법이효과가없을때약물치료를시작한다. 3) 약물치료를시작한뒤에도식이요법과운동요법을병행한다.
ADA and NCEP ATP III Recommendations for Lipid Goals in Patients Goals LDL cholesterol (mg/dl) Non-HDL cholesterol (mg/dl) ApoB (mg/dl) Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more additional major CVD risk factor <70 <100 <80 High-risk patients, including those with 1) no diabetes or known clinical CVD but two or more additional major CVD risk factors or 2) diabetes but no other major CVD risk factors <100 <130 <90 Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD ADA. Diabetes Care 2008;31:811-822
Statins: first-line therapy for reducing LDL levels in patients at high risk for atherosclerotic cardiovascular disease (ASCVD).
LDL-C ( SE) Reduction (%) Percentage Change in LDL-C: Pairwise Comparisons with Rosuvastatin Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) 0 10 20 40 10 20 40 80 10 20 40 80 10 20 40 10 20 30 40 50 60-45.8* 52.4 55.0-36.8-42.6-47.8 51.1-28.3-35.0-38.8 45.8-20.1-24.4-29.7 * P<0.001 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg P<0.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg P<0.001 vs atorvastatin 40 mg,80mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg
% Patients with CHD Event 얼마나낮출것인가? Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy 25 20 15 10 5 0 TNT-80A TNT-10A CARE-Rx ASCOT-Rx POSCH-Rx HPS-Rx 4S-Rx LIPID-Rx LIPID-PL WOSCOPS-Rx ASCOT-PL AFCAPS-Rx HPS-PL POSCH-PL CARE-PL 50 70 90 110 130 150 170 190 210 LDL cholesterol 4S-PL WOSCOPS-PL LRC-Rx AFCAPS-PL LRC-PL Primary prevention trials Secondary prevention trials HPS Statin trials non statin trials (mg/dl) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/l)
Increase of IMT Relative risk for CVD Not only LDL-C but also HDL-C are the key factor for the regression of atherosclerosis and prevention of CVD (mm/5year) 0.05 ARIC Study 3 Framingham Study 0.04 0.03 0.02 0.01 2.5 2 1.5 1 0.5 190 160-189 130-159 100-129 <100 60 50-59 40-49 <40 HDL-C(mg/dL) 0 220 160 100 85 55 25 HDL-C(mg/dL) Stephen J Nicholls et al., JAMA 2007:297:499-508 Modified from Kannel WB et al., Am Heart J 1985:110:1100-1107 Modified from Paul Muntner et al., Presented at ACC in 2007
Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
HDL-C Increase (%) Percentage Change from Baseline in HDL-C at Week 6 by Dose 12 ITT = intention-to-treat 10 9.5 9.6 8 6 7.7* 5.7 4.8 4.4 5.3 6.0 5.2 6.8 4.4 5.6 4 3.2 2 2.1 0 10 20 40 Rosuvastatin (mg) 10 20 40 80 Atorvastatin (mg) 10 20 40 80 Simvastatin (mg) 10 20 40 Pravastatin (mg) * P<0.002 vs pravastatin 10 mg P<0.002 vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg P<0.002 vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg Jones PH, et al. Am J Cardiol. 2003;92:152-160
To Study the Disease you Need to Image the Vessel Wall
Carotid Intima Medial Thickness
Change in IMT of 12 carotid sites (mm) Regression Progression A METEOR study Rate of changes of max. IMT at 12 carotid sites Rosuvastatin vs placebo +0.03 +0.02 placebo +0.0131 mm/yr (n=252) +0.01 P<0.0001 (rosuvastatin vs. placebo) 0.00 1 2 Time (years) -0.01 rosuvastatin 40 mg -0.0014 mm/yr (n=624) P=NS (rosuvastatin vs. zero slope) Placebo; change in CIMT (95% CI) Rosuvastatin 40 mg; change in CIMT (95% CI) Crouse JR III et al. JAMA 2007;297 (12):1344 1353
Ultrasound Determination of Atheroma Area Precise Planimetry of EEM and Lumen Borders with Calculation of Atheroma Cross-sectional Area EEM Area Lumen Area Atheroma Area
PAV Change PAV Atheroma Burden and Incident Clinical Events ILLUSTRATE (N=1180) Incidence of cardiovascular death, myocardial infarction, hospitalisation for unstable angina, stroke and coronary revascularisation Baseline Percent Atheroma Volume Change Percent Atheroma Volume 42.0 0.6 38.5 P<0.001 0.3 P=0.04 35.0 0.0 Yes No Yes No Nicholls S. AHA Scientific Sessions 2007
Percent change in atheroma volume REVERSAL: Benefit of Intensive LDL-C Lowering on Plaque Progression 3 Progression (P=0.001) pravastatin 40 mg 2 atorvastatin 80 mg 1 P=0.02 between treatment groups 0-1 No change (P=0.98) Nissen SE et al. JAMA 2004;291:1071 1080
Change in Atheroma Volume, REVERSAL Comparison of % LDL Cholesterol Reduction and Change in Atheroma Volume 20 15 10 mm 3 5 0-5 50% LDL-C reduction -10-15 -80-70 -60-50 -40-30 -20-10 0 10 20 % Change in LDL Cholesterol
% A ASTEROID: Regression with High Dose Statin Therapy 349 patients treated with rosuvastatin 40 mg for 2 years LDL-C 60.8 mg/dl and increase HDL-C by 14.7% Percent Atheroma Volume Atheroma Volume Most Diseased 10 mm Total Atheroma Volume 0.0 0.0 0-0.5-1.0 mm 3-2.5-5.0-0.79-5.6 P<0.001 P<0.001-7.5 mm 3-5 -10-15 -12.5 P<0.001 Nissen SE, Nicholls S et al. JAMA 2006;295:1555 1565
Median change in percent atheroma volume (%) Relationship Between LDL-C Levels and Change in Percent Atheroma Volume for Several IVUS Trials 1.8 1.2 R 2 = 0.97 P<0.001 CAMELOT placebo REVERSAL pravastatin 0.6 0-0.6 REVERSAL atorvastatin ASTEROID rosuvastatin A-Plus placebo -1.2 50 60 70 80 90 100 110 120 Mean LDL-C (mg/dl) Progression Regression Nissen S et al. JAMA 2006
Cholesterol Treatment Trialists (CTT): Relative Risk of Major Vascular Events 60% 50% 22% reduction per 1 mmol/l lower LDL-C 14 statin trials Relative risk reduction 40% 30% 20% 10% 0% 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2-10% -20% LDL cholesterol difference (mmol/l) Baigent C. Lancet 2005 Oct 8; 366:1267-78
Statin and beyond? A &
JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hscrp No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:2292-2297.
hs-crp? Lowering CRP with Statin Therapy Reduces CV Risk: PROVE-IT Study group (levels after statin) Low LDL-C/low CRP n 1018 Number recurrent events 48 Number of events/ 100 pt yr 2.4 Low LDL-C/high CRP 899 56 3.2 High LDL-C/low CRP 742 47 3.1 High LDL-C/high CRP 1086 92 4.6 Ridker PM et al. N Engl J Med 2005;352:20-28.
Cumulative Incidence JUPITER Primary Trial Endpoint: MI, Stroke, UA/Revascularization, CV Death Number Needed to Treat (NNT5) = 25 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Ridker et al. NEJM 2008;359(21):2280-2
Percentage change from baseline (%) JUPITER Effects on LDL-C, HDL-C, TG and hscrp at 12 months; Percentage change between rosuvastatin and placebo 10 LDL-C HDL-C TG hscrp 0-10 -20 4% p<0.001* 17% p<0.001-30 -40 37% p<0.001-50 -60 50% p<0.001 *P-value at study completion (48 months) = 0.34 Ridker P et al. N Eng J Med 2008;359: 2195-2207
0.000 0.005 0.010 0.015 0.020 0.025 Cumulative Incidence Artery or vein? JUPITER Total Venous Thromboembolism HR 0.57, 95%CI 0.37-0.86 P= 0.007 0 1 2 3 4 Placebo 60 / 8901-43 % Rosuvastatin 34 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182
Heart failure? Rosuvastatin in Older Patients with Systolic Heart Failure (CORONA) Hazard ratio = 0.84 (0.7-1.0) 일차종말점 ( 심혈관계사망, 비치명적심근경색, 비치명적뇌졸중의첫발생까지의시간 ) NEJM 2007. 357:2248-2261
Arteriosclerosis? CAFE-LLA: Statin therapy does not influence central aortic pressure or hemodynamics Williams, B. et al. Circulation 2009;119:53-61
A CAFÉ -BLA: Lower central aortic BP with newer vs older antihypertensive regimen despite similar brachial BP 140 135 Brachial SBP mm Hg 130 125 Central aortic SBP Atenolol ± thiazide 120 Amlodipine ± perindopril 115 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Time (years) CAFE Investigators. Circulation. 2006;113:1213-25.
Statin 안전한가? A & The Issue of Statin Safety Where do We Stand? Scott M. Grundy, MD, PhD Circulation. 2005;111:3016-3019. http://www.circ.ahajournals.org/cgi/content/full/111/23/3016
higher risk for severe myopathy advanced age (especially >80 years) (women > men) small body frame and frailty multisystem disease (eg, CRF, especially if caused by diabetes) perioperative periods multiple medications (especially gemfibrozil, cyclosporine, azole antifungals, itraconazole and ketoconazole, macrolide antibiotics, erythromycin and clarithromycin, HIV protease inhibitors, the antidepressant nefazodone, and verapamil) consumption of large quantities of grapefruit juice (>1 quart/day) alcohol abuse (which independently predisposes to myopathy) Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation. 2002; 106: 1024 1028
Deaths Due to Suicide, Cancer, and Hemorrhagic Stroke Number (%) of patients Quintile 1 <64 mg/dl (114/1722) * Quintile 2 64 <77 mg/dl (529/1403) * Quintile 3 77 <90 mg/dl (1019/968) * Quintile 4 90 <106 mg/dl (1515/515) * Quintile 5 106 mg/dl (1718/266) * Suicide 1 (0.1) 0 (0.0) 1 (0.1) 1 (0.0) 1 (0.1) Cancer 21 (1.1) 37 (1.9) 34 (1.7) 32 (1.6) 30 (1.5) Hemorrhagic stroke 6 (0.3) 5 (0.3) 6 (0.3) 8 (0.4) 7 (0.4) * Number of patients: atorvastatin 10 mg/atorvastatin 80 mg Fatal and non-fatal
Statin Safety in Perspective Number needed to treat for 1 year to: Cause a GI Bleed 1 Cause a Fatal GI Bleed 1 Aspirin 248 2066 Cause Severe Myositis 2 Cause Fatal Myositis 2 Statins 100,000 1,000,000 1 Derry S, Loke YK. 2000 2 Thompson PD, et al. 2003
Evolving of Dyslipid Vascular disease Target: LDL, HDL-chol Statins: dyslipidemia and vascular disease and so athersclerotic CV disease Statins and beyond: useful in high inflammatory condition, VTE not useful in systolic HF and arteriosclerosis Statins and safety: quite safe
The Future of Best Practice Normal plasma cholesterol 700 (18.0) - 300 (7.7) - Physiologic level for plasma LDL-chol as predicted from receptor Studies 25 mg/dl FH homozygotes FH heterozygotes 200 (5.2) - 150 (3.9) - Rat Guinea pig Sheep Cow Camel Rabbit Pig Normal adults 100 (2.6) - 50 (1.3) - Newborns 0