Lipid is evolving. Dyslipidemia Vascular disease. Statin. Beyond 관동의대제일병원 내과박정배

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1 Lipid is evolving Dyslipidemia Vascular disease Statin Beyond 관동의대제일병원 내과박정배

2 A Dyslipidemia 와혈관질환, 그연결고리는? &

3 약 80% 가 체내에서생성 약 20% 가 음식물에서흡수 Quantity of cholesterol in the body Bile acids 배설

4 동맥경화증의위험요인 흡연이고혈압의위험요인인것처럼, 혈액중에콜레스테롤의양이많으면심장질환과동맥경화의위험요인이된다. High blood cholesterol Obesity Hypertension Aging Smoking Diabetes mellitus Other Heredity Coronary Heart Disease

5 죽상경화증 (atherosclerosis) 과동맥경화증 (arteriosclerosis) Compliant Arterio and Atherosclerosis Systole Diastole Systole Diastole Constant Stroke Volume Aorta compliant stiffened Pulse pressure

6 Vascular event (MI or Stroke) rate and IMT O Leary DH et al. N Engl J Med.1999;340(1):14-22

7 Vascular event and Plaque Birgelen C et al. Circulation 2004;110:1579

8 Endothelial function test Vascular imaging Evolving of Dyslipid Vascular disease Pulse wave change (eg,augmentation index)

9 Markers of Atherosclerosis and arteriosclerosis are risk factors for adverse CV outcomes

10 8-year probability (per 1000) Risk of CHD by Multiple Risks & Cholesterol Cholesterol mg/dl (mmol/l) ( ) ( ) ( ) ( ) Glucose Intolerance Systolic BP (mmhg) Cigarettes LVH on ECG Kannel J. Am Coll Cardiol. 1990

11 Q & Dyslipidemia, 혈관질환과의연 A 결고리를어떻게끊을것인가? Dyslipidemia Vascular disease Statin & beyond

12 Benefit of Lowering Cholesterol Meta-analysis of 38 1 o & 2 o prevention trials, with 98,000 patients 0.0 Mortality log odds ratio Mortality in CHD, p=0.012 Total mortality, p= Cholesterol reduction (%) Gould AL et al. Circulation 1998;97:

13 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

14 지혈이상증의치료 약물투여 식이요법 운동 고지혈증치료의기본원칙 1) 고지혈증의종류에따라식이요법과운동처방을약 3 개월동안시행한다. 2) 식이요법과운동요법이효과가없을때약물치료를시작한다. 3) 약물치료를시작한뒤에도식이요법과운동요법을병행한다.

15 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:

16 Statins: first-line therapy for reducing LDL levels in patients at high risk for atherosclerotic cardiovascular disease (ASCVD).

17 LDL-C ( SE) Reduction (%) Percentage Change in LDL-C: Pairwise Comparisons with Rosuvastatin Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) * * 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

18 % Patients with CHD Event 얼마나낮출것인가? Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy 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 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) (mmol/l)

19 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 < <40 HDL-C(mg/dL) HDL-C(mg/dL) Stephen J Nicholls et al., JAMA 2007:297: Modified from Kannel WB et al., Am Heart J 1985:110: Modified from Paul Muntner et al., Presented at ACC in 2007

20 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

21 HDL-C Increase (%) Percentage Change from Baseline in HDL-C at Week 6 by Dose 12 ITT = intention-to-treat * Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) 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:

22 To Study the Disease you Need to Image the Vessel Wall

23 Carotid Intima Medial Thickness

24 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 placebo mm/yr (n=252) P< (rosuvastatin vs. placebo) Time (years) rosuvastatin 40 mg 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):

25 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

26 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 P< P= Yes No Yes No Nicholls S. AHA Scientific Sessions 2007

27 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:

28 Change in Atheroma Volume, REVERSAL Comparison of % LDL Cholesterol Reduction and Change in Atheroma Volume mm % LDL-C reduction % Change in LDL Cholesterol

29 % 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 mm P<0.001 P< mm P<0.001 Nissen SE, Nicholls S et al. JAMA 2006;295:

30 Median change in percent atheroma volume (%) Relationship Between LDL-C Levels and Change in Percent Atheroma Volume for Several IVUS Trials R 2 = 0.97 P<0.001 CAMELOT placebo REVERSAL pravastatin REVERSAL atorvastatin ASTEROID rosuvastatin A-Plus placebo Mean LDL-C (mg/dl) Progression Regression Nissen S et al. JAMA 2006

31 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% % -20% LDL cholesterol difference (mmol/l) Baigent C. Lancet 2005 Oct 8; 366:

32 Statin and beyond? A &

33 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:

34 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 High LDL-C/low CRP High LDL-C/high CRP Ridker PM et al. N Engl J Med 2005;352:20-28.

35 Cumulative Incidence JUPITER Primary Trial Endpoint: MI, Stroke, UA/Revascularization, CV Death Number Needed to Treat (NNT5) = 25 HR 0.56, 95% CI P < Ridker et al. NEJM 2008;359(21):2280-2

36 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 % p<0.001* 17% p< % p< % p<0.001 *P-value at study completion (48 months) = 0.34 Ridker P et al. N Eng J Med 2008;359:

37 Cumulative Incidence Artery or vein? JUPITER Total Venous Thromboembolism HR 0.57, 95%CI P= Placebo 60 / % 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, ,901 8,652 8,417 6,574 3,943 2,012 1,

38 Heart failure? Rosuvastatin in Older Patients with Systolic Heart Failure (CORONA) Hazard ratio = 0.84 ( ) 일차종말점 ( 심혈관계사망, 비치명적심근경색, 비치명적뇌졸중의첫발생까지의시간 ) NEJM :

39 Arteriosclerosis? CAFE-LLA: Statin therapy does not influence central aortic pressure or hemodynamics Williams, B. et al. Circulation 2009;119:53-61

40 A CAFÉ -BLA: Lower central aortic BP with newer vs older antihypertensive regimen despite similar brachial BP Brachial SBP mm Hg Central aortic SBP Atenolol ± thiazide 120 Amlodipine ± perindopril Time (years) CAFE Investigators. Circulation. 2006;113:

41 Statin 안전한가? A & The Issue of Statin Safety Where do We Stand? Scott M. Grundy, MD, PhD Circulation. 2005;111:

42 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:

43 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 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

44 Statin Safety in Perspective Number needed to treat for 1 year to: Cause a GI Bleed 1 Cause a Fatal GI Bleed 1 Aspirin Cause Severe Myositis 2 Cause Fatal Myositis 2 Statins 100,000 1,000,000 1 Derry S, Loke YK Thompson PD, et al. 2003

45 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

46 The Future of Best Practice Normal plasma cholesterol 700 (18.0) (7.7) - Physiologic level for plasma LDL-chol as predicted from receptor Studies 25 mg/dl FH homozygotes FH heterozygotes 200 (5.2) (3.9) - Rat Guinea pig Sheep Cow Camel Rabbit Pig Normal adults 100 (2.6) - 50 (1.3) - Newborns 0