Clinical advances in intensive cholesterol management in patients with cardiometabolic risk factors

Transcription

1 Clinical Implications from Recent Lipid Guideline for High-risk Patients Chang-Wook NAM, MD, PhD Keimyung University Dongsan Medical Center

2 I have nothing to disclosure for this presentation. The view expressed herein represents those of the speaker and not necessarily those of the MSD Korea.

3 Agenda 1. Benefits of combination therapy aligned with recent update guidelines Recent update guideline and Implications Benefits of ezetimibe/statin combination therapy for LDL-C reduction 2. New considering point of view for preventing Atherosclerosis CRP Chylomicron and ApoB in atherosclerosis Further clinical outcomes of combination therapy

4 1. Benefits of combination therapy aligned with recent update guidelines Recent update guideline and Implications Benefits of ezetimibe/statin combination therapy for LDL-C reduction

5 Events Rate (%) Relationship Between LDL-C on Treatment and Clinical Event Rates in Major Trial 4S 4S Secondary Prevention PROVE-IT (Atv) CARE LIPID IDEAL IDEAL (Sim) HPS TNT (Atv) (Atv 10 mg) HPS PROVE-IT (Pra) TNT AFCAPS (Atv 80 mg) ASCOT ASCOT CARE AFCAPS Mean Treatment LDL-C at Follow-up (mg/dl) LIPID WOSCOPS WOSCOPS Primary Prevention Atv = atorvastatin; Pra = pravastatin; Sim = simvastatin; PROVE-IT = Pravastatin or AtorVastatin Evaluation and Infection Therapy; IDEAL = Incremental Decrease in Endpoints through Aggressive Lipid Lowering; ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; AFCAPS = Air Force Coronary Atherosclerosis Prevention Study; WOSCOPS = West of Scotland Coronary Prevention Study 1. Rosenson RS. Expert Opin Emerg Drugs. 2004;9: LaRosa JC, et al. N Engl J Med. 2005;352:

6 LDL-C Goals for High-Risk Patients Have Become More Intensive As part of therapeutic lifestyle changes, including diet, LDL-C treatment goals for high-risk patients have been lowered over time 1988 ATP I 1993 ATP II 2001 ATP III 2004 ATP III Update AHA/ACC 2010 ADA 2011 ESC/EAS Goal: <130 mg/dl 1 Goal: 100 mg/dl 2 Goal: <100 mg/dl 3 Goal: Goal: Goal: <100 mg/dl 4 <100 mg/dl 5 <100 mg/dl 6 Very-high-risk pts Optional goal: <70 mg/dl 4 High-risk pts Reasonable goal: <70 mg/dl 5 Overt CVD <70 mg/dl 6 Very high risk pts Goal: <70 mg/dl 7 Familial dyslipidemia, severe HTN <100 mg/dl 7 Definition of high-risk / highest-risk or very high patient: ATP I: definite CHD or 2 other CHD risk factors 1 ATP II: existing CHD or other atherosclerotic disease 2 ATP III and the 2004 update: CHD or CHD risk equivalents 3,4 2 AHA/ACC 2006: established coronary and other atherosclerotic disease 5 ADA 2010: overt CVD 6 ESC/EAS 2011: CVD (MI, ACS, revascularization), ischemic stroke, type 2 DM, moderate to severe CKD, or SCORE 10% 7 CHD: coronary heart disease, CVD: cardiovascular disease, MI: myocardial infarction, ACS: acute coronary syndrome, CKD: chronic kidney disease, HTN: hypertension 1. NCEP ATP I. Arch Intern Med. 1988;148:36 69; 2. NCEP ATP II. JAMA. 1993;269: ; 3. NCEP ATP III. JAMA. 2001;285: ; 4. Grundy SM et al. Circulation. 2004;110: ; 5. Smith SC Jr et al. Circulation. 2006;113: ; 6. ADA. Diabetes Care. 2010;33(suppl 1):S11 S Reiner Z. et al. European Heart Journal 2011;32:

7 Very high risk in updated ATPIII Established CVD plus Multiple major risk factors (especially DM) Severe and poorly controlled risk factors (especially continued smoking) Multiple risk factors of MetS (especially Tg 200, Non-HDL-c 130, and HDL-c <40) Acute coronary syndrome LDL-c goal <70mg/dL In high risk persons (10yr CHD risk >20%), LDL-c goal <100 mg/dl if LDL-c 100mg/dL, LDL-c lowering drug is indicated if LDL-c <100mg/dL, LDL-c lowering drug is an option When TG 200mg/dL, non-hdl-c is secondary target of therapy, with a goal 30mg/dL higher than LDL-c goal When LDL-c lowering drugs are used, LDL-c levels should be reduced at least 30-40%

8 Current status of NCEP ATP IV (As of Feb.13) The following table reflects the status of each report and progress through the remaining stages of the review process before the guidelines are released. Draft Finished Federal Review Expert Review Advisory Council Public Comment HHS Clearance Release Lifestyle Completed Completed Completed In Progress Risk Assessment Completed Completed Completed In Progress Cholesterol Completed Completed Completed In Progress Blood Pressure Obesity In Progress In Progress Draft Completed: Expert panelists have completed a full draft of the systematic review and recommendations. Federal Review: Federal agency representatives of the NHLBI's National Program to Reduce Cardiovascular Risk (NPRCR) coordinating committee provide review and comment. Expert Review: External peer reviewers with expertise in the relevant risk factors provide review and comment. Advisory Council: The National Heart, Lung, and Blood Advisory Council provides review and comment and recommends approval. Public Comment: The draft is offered publicly for review and comment. HHS Clearance: The U.S. Department of Health and Human Services provides editorial review, comment, and approval.

9 ESC/EAS 2011 Guidelines : Very High and High CV Risk Level Classification 1 Very High Risk includes subjects with any of the following: Documented CVD, previous MI, ACS, coronary revascularization, other revascularization procedure, ischemic stroke, PAD Type 2 diabetes or type 1 diabetes with target organ damage (such as microalbuminuria) Moderate to severe CKD (GFR <60 ml/min/1.73 m 2 ) A calculated 10-year risk SCORE 10% High Risk includes subjects with any of the following: Markedly elevated single-risk factors (eg, familial dyslipidemias or severe hypertension) A calculated 10-year risk SCORE 5% and <10% for fatal CVD Patients with VERY HIGH or HIGH total CV risk need active management of all risk factors. For all other people, the use of a risk estimation system such as SCORE is recommended to estimated total CV risk. CVD = cardiovascular disease; MI = myocardial infarction; ACS = acute coronary syndrome; PAD = peripheral artery disease; CKD = chronic kidney disease; GFR = glomerular filtration rate; SCORE = Systematic Coronary Risk Estimation. 1. Reiner Z et al. Eur Heart J. 2011;32:

10 ESC/EAS 2011 Guidelines: Lipid Targets 1 More aggressive target for high-risk patients LDL-C Non HDL-C Apo B Primary Target Secondary Targets Very high risk <1.8 mmol/l Documented CVD, previous MI, ACS, coronary or other arterial revascularization, ischemic stroke, PAD, type 2 diabetes or type 1 diabetes with target organ damage, moderate to severe CKD, or a calculated 10 year risk SCORE 10% (~70 mg/dl) And/or 50% reduction from baseline <2.6 mmol/l (~100 mg/dl) <80 mg/dl High risk Markedly elevated single risk factors such as familial dyslipidemia and severe hypertension, or a calculated SCORE 5% and <10% for 10 year risk of fatal CVD <2.5 mmol/l (~100 mg/dl) <3.3 mmol/l (~130 mg/dl) <100 mg/dl Moderate risk SCORE is 1% and <5% at 10 years <3.0 mmol/l (~115 mg/dl) <3.8 mmol/l (~145 mg/dl) Not defined ESC/EAS = European Society of Cardiology/European Atherosclerosis Society; apo = apolipoprotein; CVD = cardiovascular disease; MI = myocardial infarction; ACS = acute coronary syndromes; PAD = peripheral artery disease; CKD = chronic kidney disease; SCORE = Systematic Coronary Risk Estimation. 1. Reiner Z et al. Eur Heart J. 2011;32:

11 ESC/EAS 2011 Guidelines: Management of Dyslipidemia in Acute Coronary Syndrome 1 High dose statin therapy be initiated during the first 1 4 days of hospitalization for the index ACS; if basal LDL-C values are known, the dose should aim at reaching the LDL-C target of <1.8 mmol/l (less than ~70 mg/dl). The use of lower intensity statin therapy should be considered in patients at increased risk of side effects with high doses of statin (e.g. the elderly, hepatic impairment, renal impairment, or potential for interaction with essential concomitant therapy). Lipids should be re-evaluated 4 6 weeks after the ACS to determine whether target levels have been reached and regarding safety issues; the statin dose can then be adapted accordingly. ESC/EAS = European Society of Cardiology/European Atherosclerosis Society. 1. Reiner Z et al. Eur Heart J. 2011;32:

12 1. Steg European Heart Journal 2012; ESC/EAS 2011 Guidelines: Management of Acute myocardial infarction with ST-segment elevation 1 Statins should be given to all patients with acute myocardial infarction, irrespective of cholesterol concentration. The use of lower-intensity statin therapy should be considered in patients at increased risk of side-effects from statins. e.g. the elderly, patients with hepatic or renal impairment, with previous side-effects of statins or the potential for interaction with essential concomitant therapy In patients known to be intolerant of any dose of statin, treatment with ezetimibe should be considered

13 ESC/EAS 2011 Guidelines: Management of Dyslipidemia in the Elderly 1 Statins are recommended for elderly patients with established CVD in the same way as for younger patients [Class I, Level B]. Since elderly patients often have comorbidities and have altered pharmacokinetics, it is recommended to start lipid-lowering medication at a low dose and then titrate with caution to target lipid levels, which are the same as in younger subjects [Class I, Level C]. Statin therapy may be considered in elderly subjects without CVD, particularly in the presence of at least 1 other CV risk factor aside from age [Class IIb, Level B]. Class: Class of recommendation, Level: Level of evidence, CV: cardiovascular ESC/EAS = European Society of Cardiology/European Atherosclerosis Society. 1. Reiner Z et al. Eur Heart J. 2011;32:

14 VYTORIN (ezetimibe/simvastatin): Dual Action in Cholesterol Metabolism 33% Dietary chol Cholesterol Pool (Micelles) 67% Biliary chol Free Chol Liver : STATIN Bile Acids Acetyl CoA Chol Peripheral Tissues Intestine : EZETIMIBE NPC1L1 Remnant receptors Cholesterol Pool LDLR VLDL Hepatic Apo B-100 CMR ldl Fecal sterols CM Intestinal Apo B-48 Atheroma LDL Blood Cohen DE, Armstrong EJ. In: Principles of pharmacology: The pathophysiologic Basis of Drug Therapy. 2 nd ed. Philadelphiak PA:Lippincott, Williams &

15 Ezetimibe add-on vs. Statin doubling in LDL-C lowering Simvastatin 10 mg 20 mg 40 mg 80 mg Simvastatin 10 mg Ezetimibe 10 mg 1. Bays et al. Clin ther. 2004;26: ; 2. Bays H, Dujovne C. Expert Opin Pharmacother 2003;4:

16 Based on 3 Separate Clinical Studies, More Dosing Options of VYTORIN (ezetimibe/simvastatin) Provided 50% Mean LDL-C Reduction vs Other Selected LDL-C Lowering Drugs Dose achieving 50% mean LDL-C reduction 1-4 (individual responses vary) The above comparisons do not establish that the products have the same indications, safety profiles, or dosing regimens Q Korea IMS Q; 2. Bays HE et al. Clin Ther. 2004;26: ; 3. Ballantyne CM et al. Am Heart J. 2005;149: ; 4. Catapano AL et al. Curr Med Res Opin. 2006;22:

17 Mean percent change from baseline at 6 weeks (%) In hypercholesterolemia patients VYTORIN 10/20mg provided 50% reduction in LDL-C 1 In a clinical study of patients with hypercholesterolemia and type 2 DM (VYTAL study) # # LDL-C TC HDL-C TG non-hdl-c hs-crp 20% 10% 0% -10% -20% -30% -40% -50% -60% -54% -45% P< % -33% P< % P= % -26% -26% -48% -41% P< % -14% VYTORIN 10/20mg (n=238) Atorvastatin 20mg (n=240) HDL-C: high-density lipoprotein cholesterol, hs-crp: high-sensitivity C-reactive protein, LDL-C: low-density lipoprotein cholesterol, TC: total cholesterol, TG: triglycerides #: median 1. Goldberg RB, et al. Mayo Clin Proc. 2006;81(12):

18 Mean percent change from baseline (%) Mean percent change from baseline at week 6 (%) Statin treated, but Not at LDL-C goal, Switching to VYTORIN 10/20mg provided 25% reduction in LDL-C 1 5% 0% # # LDL-C TC HDL-C TG non-hdl-c ApoB hs-crp 2% 3% 0% -5% -5% -10% -15% -10% -11% -14% -10% -8% -20% -17% -18% P % P % -30% -28% P % P VYTORIN 10/20mg (n= ) Rosuvastatin 10mg (n= ) Apo: apolipoprotein, HDL-C:high-density lipoprotein cholesterol, hs-crp: high-sensitivity C-reactive protein, LDL-C: lowdensity lipoprotein cholesterol, TC: total cholesterol, TG: triglycerides #: median 1. Farnier M, et al. Int J Clin Pract. 2009;63(4):

19 VYTORIN was Generally Well Tolerated 1,2 All VYTORIN 10/20, 10/40mg/day (n= ) Statin untreated 1 Statin treated, not at goal 2 All atorvastatin 10, 20, 40mg/day (n= ) VYTORIN 10/20 mg/day Rosuvastatin 10 mg/day Adverse Events (n=314) 1 Clinical event 19.8% 22.7% 7.1% 11.2% (n=304) Drug-related clinical event 4.0% 4.1% 2.6% 3.3% Discontinuation due to drug-related clinical event ALT and/or AST 3 ULN (consecutive) 0.2% 1.0% 2.2% 1.0% 0 0.4% 0.7% 0 CK 10X ULN 0 0 CK 5X ULN 0 0 Adapted from Goldberg RB,et a and Farnier M. et al ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; CK=creatine kinase. 1. Goldberg RB, et al. Mayo Clin Proc. 2006;81(12): / 2. Farnier M, et al. Int J Clin Pract. 2009;63(4):

20 Rapid LDL-C reduction with VYTORIN in hyperlipidemia patients with AMI 60 admitted AMI patients were randomized to simvastatin 40 mg, VYTORIN(ezetimibe/simvastatin) 10/40mg or NLLD and had their lipid levels assessed 2, 4 and 7 days later. AMI= acute myocardial infarction; NLLD= no lipid-lowering drugs; LDL-C= low density lipoprotein-cholesterol. 1. Chenot F, et al. Eur J Clin Invest 2007; 37 (5):

21 Benefit of Early Start of VYTORIN Rapid LDL-C target goal achievement with VYTORIN in AMI patients. 45% target goal reached on the 4 th day! Percentage of patients achieving a goal LDL-C level of < 70 mg dl 1 during treatment with NLLD(n=20), simvastatin 40 mg/day(n=20), or ezetimibe 10 mg/day co-administered with simvastatin 40 mg/day(eze/simva, n=20) after an AMI. AMI= acute myocardial infarction; NLLD= no lipid-lowering drugs; LDL-C= low density lipoprotein-cholesterol. 1. Chenot F, et al. Eur J Clin Invest 2007; 37 (5):

22 Ezetimibe add-on to any statin provided additional 25-31% reduction of LDL-C in diabetes 1. Pearson TA et al. Mayo Clin Proc 2005;80:587-95; 2. Gagné C et al. Am J Cardiol 2002;90: ; 3. Farnier M et al. Int J Cardiol 2005;102:327-32; 4. Brohet C et al. Curr Med Res Opin 2005;20:571-8; 5. Cruz-Fernández JM et al. Int J Clin Pract 2005;59: % -1% -4% -4% -4% -26% -25% -25% -27% -31%

23 LDL-C lowering with initial statin dose Ezetimibe/Statin vs. monostatin -14.1% 1. Mikhailidis Curr Med Res Opin 2011;

24 LDL-C lowering with initial dose failure Ezetimibe add on vs. doubling statin -15.3% 1. Mikhailidis Curr Med Res Opin 2011;

25 LDL-C goal attainment with initial statin dose Ezetimibe/Statin vs. monostatin Eze/Simva combination therapy was better than mono statin in achieving LDL-C goal attainment X Mikhailidis Curr Med Res Opin 2011;

26 LDL-C goal attainment with initial dose failure Ezetimibe add on vs. doubling statin Mikhailidis Curr Med Res Opin 2011;

27 2. New considering point of view for preventing Atherosclerosis CRP Chylomicron and ApoB in atherosclerosis Further clinical outcomes of combination therapy

28 Atherosclerosis is the Most Common Pathologic Condition Leading to Cardiovascular Disease 1 A dynamic disease process clinically characterized by narrowing of the arterial lumen due to accumulation of atherogenic lipoproteins Mainly due to a complex interaction of lipoproteins, inflammation, and the arterial wall 1. Sherer Y et al. Nat Clin Pract Rheumatol. 2006;2:

29 Prolonged retention leads to ApoB modification Endothelium Interaction between lipoproteins and subendothelial matrix molecules promotes retention 1 Prolonged retention leads to LDL modification (eg, oxidation, a lipolysis, aggregation) 2 Retained lipoprotein Proteoglycan Modified ApoB lipoprotein ApoB = apolipoprotein B. a Results from prospective clinical trials do not show a benefit of antioxidants in treating atherosclerosis Tabas I et al. Circulation. 2007;116: Khalil MF et al. Arterioscler Thromb Vasc Biol. 2004;24: Jialal I et al. Circulation. 2003;107:

30 1. Tabas I et al. Circulation. 2007;116: Steinberg D et al. N Engl J Med. 1989;320: ; 3. Hansson GK. J Thromb Haemost. 2009;7(Suppl 1): Modified ApoB triggers a series of maladaptive inflammatory response Monocyte Monocytes bind to adhesion molecules Attracts circulating monocytes, which differentiate into macrophages Inhibits macrophage egress and enhances macrophage uptake of ApoB lipoproteins Causes endothelial activation Expanded intima Macrophage

31 Lipoprotein retention accelerates maladaptive inflammatory response Intima SMCs Growth factors Macrophages ingesting modified lipoproteins and forming foam cells 1 Cytokines T-cell Other immune cells entering lesion 1 Release of growth factors and cytokines from foam cells 2 Macrophage Foam cell SMC = smooth muscle cell. 1. Tabas I et al. Circulation. 2007;116: Sherer Y et al. Nat Clin Pract Rheumatol. 2006;2:

32 Lesion progresses give rise to necrotic areas Fibrous cap SMCs Immune cells further contribute to inflammatory response SMCs migrate into intima Fibrous cap forms Macrophages begin to die and give rise to necrotic areas Mast cell Dying macrophage SMC Proliferation Plaque necrosis with cholesterol crystals SMC = smooth muscle cell. 1. Tabas I et al. Circulation. 2007;116:

33 hs-crp lowering was related to LDL-C lowering Plot of Change in CRP by change in LDL 1. Kinlay J Am Coll Cardiol 2007; ,

34 1. Sager PT et al. Atherosclerosis 2005;179: hs-crp lowering was related to LDL-C lowering Strong efficacy of VYTORIN in hs-crp reduction

35 Strong efficacy in hs-crp reduction Effect of baseline hs-crp levels at clinically meaningful strata on the hs-crp response to treatment with simvastatin monotherapy(pooled across doses), and ezetimibe 10mg+simvastatin(pooled across doses). 1. Sager PT et al. Atherosclerosis 2005;179:

36 Inflammation markers were significantly improved by VYTORIN Arms : 10 mg/d of ezetimibe, 20 mg/d of simvastatin, 40 mg/d of simvastatin and 10 mg/d of ezetimibe Duration : 12 wks Pts: 178 pts with hypercholesterolemia High-sensitivity C-reactive protein (mg L -1 ) Placebo Ezetimibe(10 mg) Simvastatin(40 mg) Ezetimibe + simvastatin(10/40 mg) Baseline 3.2 ± ± ± ± 0.4 After 4 weeks 3.3 ± 0.3(3) 2.8 ± 0.3(-18) 2.5 ± 0.2(-22) a,d 2.0 ± 0.4(-43) c,f After 12 weeks 3.4 ± 0.5(6) 2.7 ± 0.4(-19) 1.9 ± 0.2(-42) c,f,h,l 1.1 ± 0.2(-69) c,f,i,k,n Intercellular adhesion molecule 1 (ng ml -1 ) Baseline 302 ± ± ± ± 35 After 4 weeks 306 ± 24(1) 253 ± 31(-17) 236 ± 18(-23) a,d 202 ± 24(-32) c,f After 12 weeks 308 ± 26(2) 247 ± 23(-19) 196 ± 15(-36) c,f,g,l 147 ± 16(-51) e,f,i,j,m TNF-α release (ng ml -1 ) Baseline 348 ± ± ± ± 38 After 4 weeks 361 ± 33(4) 305 ± 28(-16) 280 ± 25(-23) a,d 241 ± 22(-33) b,f After 12 weeks 365 ± 31(5) 298 ± 32(-17) 220 ± 21(-40) c,f,g,l 175 ± 23(-51) c,f,i,j,m IFN-γ release (ng ml -1 ) Baseline 53.2 ± ± ± ± 6.4 After 4 weeks 52.8 ± 7.4(-1) 45.6 ± 3.7(-16) 41.6 ± 3.5(-24) a,e 36.7 ± 5.1(-31) b,f After 12 weeks 52.4 ± 4.4(-2) 44.5 ± 4.5(-18) 32.7 ± 3.2(-40) c,f,h,l 24.8 ± 2.2(-53) c,f,i,j,m IL-2 release (ng ml -1 ) Baseline 5.5 ± ± ± ± 0.5 After 4 weeks 5.5 ± 0.5(0) 4.6 ± 0.5(-18) 4.5 ± 0.3(-22) a,d 3.9 ± 0.4(-32) c,f After 12 weeks 5.7 ± 0.5(4) 4.5 ± 0.5(-19) 3.7 ± 0.2(-36) c,f,g,l 2.9 ± 0.3(-49) c,f,i,j,m Data represent the mean ± SD. Values in parentheses represent percentage changes from baseline values. a P<0.05, b P<0.01, c P<0.001 vs. control group. d P<0.05, e P<0.01, f P<0.001 vs. pretreatment values. g P<0.05, h P<.001, i P<0.001 vs. ezetimibe-treated patients. j P<0.05, k P<0.001 vs. simvastatin-treated patients. i P<0.05, m P<0.01, n P<0.001 vs. the effect after 4 weeks of treatment. *Only data from subjects who completed the study were included in the final analyses. 1. Krysiak R Journal of InternalMedicine 2012;

37 2. New considering point of view for preventing Atherosclerosis CRP Chylomicron and ApoB in atherosclerosis Further clinical outcomes of combination therapy

38 1. Cohen DE, Armstrong EJ. In: Principles of pharmacology: The pathophysiologic Basis of Drug Therapy. 2 nd ed. Philadelphiak PA:Lippincott, Williams & Wilkins; 2007: ; 2. Wang DQH. Annu Rev Physiol. 2007;69: Cholesterol homeostasis 33% Dietary chol Cholesterol Pool (Micelles) 67% Biliary chol Free Chol Bile Acids Acetyl CoA Chol Cholesterol Pool LDLR Hepatic Apo B-100 Peripheral Tissues NPC1L1 Remnant receptors VLDL CMR ldl Fecal sterols CM Intestinal Apo B-48 Atheroma LDL Blood

39 ApoB-containing lipoproteins are atherogenic ApoB-containing lipoproteins (chylomicron, chylomicron remnants, VLDL, VLDL remnants, IDL, large buoyant LDL, and small, dense LDL) are atherogenic 3 Atherogenic Anti-atherogenic LDL-C Chylomicrons TG C apob-48 Chylomicron remnants TG C apob-48 VLDL TG C apob- 100 IDL TG C apob- 100 Large buoyant LDL C apob- 100 Small dense LDL C apob- 100 Lp(a) C apob- 100 HDL C apo AI ApoB-containing lipoprotein Apo = apolipoprotein; VLDL = very low-density lipoprotein; IDL = intermediate-density lipoprotein; TG = triglyceride; C = cholesterol. a Except in the presence of insulin resistance and/or metabolic syndrome Kastelein JJ et al. Circulation. 2008;117: Walldius G et al. J Intern Med. 2004;255: Robinson JG. J Am Coll Cardiol. 2009;55: Mudd JO et al. J Am Coll Cardiol. 2007;50: Kinoshita M et al. J Atheroscler Thromb. 2009;16:

40 ApoB concentration is in positive correlation with CVD 1. Emerging Risk Factors Collaboration JAMA. 2009;302(18)

41 ApoB 48-containing lipoprotein, Possible significant atherogenic risk factor Fewer numbers of ApoB 48-containing particles are retained within the intima relative to ApoB 100-containing particles (Approximately 10-fold less) In human, ApoB 48-contatining chylomicron remnants contain approximately 40 times more cholesterol per particle than do ApoB 100-containing LDL particles Normal Rabbit * *p< p< apob 48 lipoproteins (n=12) apob 100 lipoproteins (n=12) ApoB 100 containing LDL in red ApoB 48 containing Chylomicron remnant in yellow 1. Proctor et al. Current Opinion in Lipidology 2002, 13:

42 Chylomicron (apob48) occupied significantly larger area of human carotid atherosclerotic plaques, compared to hepatic apob100 Objective : To evaluate relative quantification of apob100 and apob48 in plaque. Design : DS-IF for apob100 and apob48 was performed on 4 human carotid plaques from the lesion and proximal and distal regions Results : Compared to apob100, ApoB48-positive area was significantly larger in proximal, mid and distal sections (70% vs 5%, 53.4% vs 16.2% and 55% vs 9.3%, respectively; p<0.001 for all) 1. Vazquez-Figueroa Circulation. 2010;122 A16886.

43 Macrophage change to foam cell formation by CM remnant Lipid taken up from CMRs, regardless of their oxidative state, is not readily cleared from the cells by efflux (cholesterol) or metabolism (TAG) This may be due to the sequestration of the lipid in lysosomes after their uptake by the cells. This resistance of the lipid to removal from macrophages, therefore, is another factor which is likely to contribute to the atherogenicity of CMRs. The bottom left panel shows the cells only, the top left shows the DiI fluorescence, the top right the FITC fluorescence and the bottom right the DiI and FITC fluorescence merged. The yellow color indicates co-localization of LAMP-1 and CRLPderived lipid. CRLPs : Chylimicron remnant lipoproteins LAMP-2 : lysosomalassociated membrane protein-1 1. Botham K.M et al. Biochemical Society Transactions 2007;35:

44 Both hepatic apob100 and intestinal apob48 co-localize with macrophages in human carotid atherosclerotic plaques Objective : To evaluate co-localization of apob48 and apob100 with macrophages. Design : In 3 patients undergoing carotid endarterectomy (CEA), plaques were stained for apob100/cd68 and apob48/cd68 dual stain (DS)-IF Results : (A,D) Both apob100 and apob48 are present in plaques. (C,F) while CD68 staining is present throughout the plaque and in areas independent of apob100 and apob48, both apob100 and apob48 are always co-localized with CD68. Single stain immunofluorescence(ss-if) demonstrates the distribution of intestinal apob48; Hepatic-apoB100(red)(A, D) and macrophages-cd68(blue)(b, E); Dual stain immunofluorescence(ds-if) showing co-localization of apob48 and apob100 with macrophages(purple) in human carotid artery(c, F) 1. Vazquez-Figueroa E542 JACC 2012;59

45 Chylomicron remnant can induce form cell formation without the need to become modified, in contrast to native LDL Chylomicron remnants have multiple direct effects on three major cell types of the arterial wall which are likely to promote the development of atherosclerotic lesions These effects may be modulated by various lipids carried by the particles, including the type of fat (saturated or unsaturated or oxidized fat) CM may be the most atherogenic lipoproteins in human physiology and therefore CMR accumulation should be considered a relevant factor contributing to CV risk. THP-1 macrophages were incubated with or without oxldl, CRLPs or oxcrlps (30mg cholesterol/ml) for 48 h and the cholesterol (C), cholesteryl ester (CE), triacylglycerol (TG) and total lipid (TL = C + CE + TG) content of the cells was determined. (P<0.01 three lipoprotein types vs. control cells) LDL, low density lipoprotien, CV, cardiovascular. 1. Botham KM et al. Current Pharmaceutical Design 2005;11:

46 Ezetimibe/statin reduced migration of macrophage Beneficial effects of ezetimibe 1. atherosclerosis progression 2. depletion of plaque lipid and macrophages & contributing to the plaque stabilization Immunolocalization of monocyte chemoattractant protein-1 (MCP-1) on femoral arteries from normolipidemic diet (ND, A), untreated (B), ezetimibe-treated (Eze, C), simvastatin-treated (Simva, D) and ezetimibe + simvastatin-treated (Eze + Simva, E) rabbits. *P < 0.05 versus untreated rabbits. 1. Gómez-Garre British Journal of Pharmacology 2009;

47 SANDS (Stop Atherosclerosis in Native Diabetics Study) 499 men and women with diabetes and no CVD 40 yrs old SBP>130, LDL>100 Standard Targets LDL-C <100; SBP <130 non-hdl-c <130 N=247 Aggressive Targets LDL-C <70; SBP <115 non-hdl-c <100 N=252 Measure CVD using carotid and cardiac ECHO at baseline 18 months and after 3 yrs intervention Primary outcome change in CIMT 1. Howard et al. JAMA. 2008;299(14):

48 1. Fleg JL et al. J Am Coll Cardiol. 2008;52:2198. SANDS (Stop Atherosclerosis in Native Diabetics Study) Trial Study population: Native Americans (>40 years of age) with type 2 diabetes (N=499) Lipid lowering therapy at enrollment: 37% - 44% on statins 4% - 7% on fibrates 0 2% on niacin 0 2% on fish oil Treatment duration: 3 years Primary endpoint: mean change in cimt Tx arm Baseline LDL-C (mg/dl) Endpoint LDL-C (mg/dl) Change (%) Usual care Aggressive Tx Statin only EZE + statin *P-value for change in cimt for both active treatment arms vs usual care group

49 1. Fleg JL et al. J Am Coll Cardiol. 2008;52:2198. SANDS (Stop Atherosclerosis in Native Diabetics Study) Trial Mean cimt

50 VYCTOR (VYTORIN on cimt and Overall Arterial Rigidity) Study Population: Mexican patients years of age with 10-year absolute risk for CD or MI >20% (N=90) Majority of patients on prior low-dose statins No prior use of ezetimibe Treatment Duration: 12 months Primary endpoint: change in mean cimt Tx arm Baseline LDL-C (mg/dl) Endpoint LDL-C (mg/dl) Change (%) Pravastatin 40 mg ± EZE 10 mg A Simvastatin 40 mg or 80 mg B Simvastatin 20 mg or 40 mg C + EZE 10 mg A: EZE added in month 2 if goal was not attained B. Simva titrated to 80mg in month 2 if goal was not attained C. EZE/Simva titrated to 10/40mg in month 2 if goal was not attained 1. Meaney et al. Journal of Clinical Pharmacology, 2009;49:

51 VYCTOR (VYTORIN on cimt and Overall Arterial Rigidity) Study Mean cimt P<0.01* vs baseline CD = Coronary death; MI = Myocardial infarction * P value for intragroup analysis for 12 month vs baseline cimt for all groups Meaney et al. J Clin Pharmacol. 2009;49:

52 Same cimt regression, but low discontinuation Group No Goal Attainment Raise of CPK Abandonment Rash Myalgia Total Pravastatin 40 ±Ezetimibe 10mg 8 a Simvastatin 40 or 80mg 4 b 3 c VYTORIN 10/20 or 10/40mg 4 d e 0 7 Total CPK, creatine phosphokinase, 5 times higher than normal reference values. All secondary effects in group B occurred with 80 mg of simvastatin. a. Pravastatin 40 mg + ezetimibe 10 mg. b. Simvastatin 80 mg. c. Simvastatin 40 mg. d. Simvastatin + ezetimibe 40/10 mg. e. Simvastatin + ezetimibe 20/10 mg. Meaney et al. J Clin Pharmacol. 2009;49:

53 2. New considering point of view for preventing Atherosclerosis CRP Chylomicron and ApoB in atherosclerosis Further clinical outcomes of combination therapy

54 Reduction of Ischemic Cardiovascular Events in SEAS trial RR 47% RR 36% SEAS T1 SEAS T2 In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, combined ezetimibe (10 mg) and simvastatin (40 mg) decreased lowdensity lipoprotein cholesterol levels by 50% and ischemic cardiovascular event (ICE) risk by 22% compared to placebo. SEAS T3 In JV tertiles 1(baseline mean JV=2.5m/s) and 2(3.1m/s), ICE risk decreased by 47% and 36%, respectively, was reasonably well predicted by all LCs, and was consistent with findings from metaregression analyses in other populations. (JV terriles 3: 3.7m/s) 1. Holme Am J Cardiol 2010;

55 SHARP: Eligibility and Key outcome The effects of lowering LDL cholesterol with Simvastatin plus Ezetimibe in patients with chronic kidney disease (Study of Heart And Renal Protection : SHARP) History of chronic kidney disease not on dialysis: elevated creatinine on 2 occasions Men: 1.7 mg/dl (150 µmol/l) Women: 1.5 mg/dl (130 µmol/l) on dialysis: haemodialysis or peritoneal dialysis No history of myocardial infarction or coronary revascularization Key outcome Composite of major atherosclerotic events including Coronary death, Non-fatal MI Non-haemorrhagic stroke Any revascularization 1. SHARP Collaborative Group Am Heart J 2010;0:1-10.e10

56 SHARP: Study of Heart And Renal Protection Simvastatin + ezetimibe (n=4,650) Placebo (n=4,620) Previous vascular disease* 711 (15%) 682 (15%) Diabetes* 1,054 (23%) 1,040 (23%) Men 2,915 (63%) 2,885 (62%) Age at randomisation (years)* 62 (12) 62 (12) Total cholesterol (mmol/l) 4.88 (1.20) 4.90 (1.17) LDL cholesterol (mmol/l) 2.77 (0.88) 2.78 (0.87) HDL cholesterol (mmol/l) 1.12 (0.35) 43 mg/dl 1.11 (0.34) Triglycerides (mmol/l) 2.31 (1.76) 204 mg/dl 2.34 (1.68) Renal status 189 mg/dl 107mg/dL On dialysis 1,533 (33%) 1,490 (32%) Haemodialysis 1,275 (27%) 1,252 (27%) Peritoneal dialysis 258 (6%) 238 (5%) Not on dialysis 3,117 (67%) 3,130 (68%) Data are n (%), mean (SD), or median (IQR). MDRD=Modifi ed Diet in Renal Disease.17 GFR=glomerular fi ltration rate. *Variables updated at 1 year for patients originally allocated simvastatin only who were rerandomised to simvastatin plus ezetimibe or placebo. Five versus fi ve patients received a transplant before rerandomisation. 1. Colin Baigent Lancet 2011;

57 SHARP: Major Atherosclerotic Events composite endpoint coronary death, non-fatal MI, non-hemorrhagic stroke and any revascularization 2.1% Absolute Risk Reduction 13 4% 11 3% 1. Colin Baigent Lancet 2011;

58 SHARP: Major Atherosclerotic Events composite endpoint 28% 21% Ezetimibe/Simvasatin better Placebo better 1. Colin Baigent Lancet 2011;

59 SHARP: Safety Myopathy Hepatitis

60 Event reduction based upon the level of LDL-C reduction of ezetimibe/statin and the Cholesterol Treatment Trialists Vascular Health and Risk Management 2012:

61 IMPROVE-IT: IMProved Reduction of Outcomes: Vytorin Efficacy International Trial Patients stabilized post-acs 10 days LDL-C 125mg/dL (or 100mg/dL if prior statin) Double-blind ASA+ Standard Medical Therapy N=18,000 Simvastatin 40 mg* Ezetimibe/Simvastatin 10/40mg* Follow-up visit day 30, every 4 months Duration: Minimum 2 ½ year follow-up (5,250 events) Primary Endpoint: CV Death, MI, Hospital Admission for UA, Revascularization (>30 days after randomization), or Stroke LDL-C, low density lipoprotein-cholesterol; CV, cardiovascular; MI, Myocardial infarction; UA, unstable angina 1. Cannon et al. American Heart Journal. 2008;156:

62 Take Home Messages Ezetimibe and Statin Fixed dose combination might be smart option for managing dyslipidemia in high risk patients 1. Ezetimibe/Statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis marker 1 2. ESC/ESA 2011 recommends more aggressive lipid target for very high-risk patients [< 1.8 mmol/l(~70 mg/dl) And/or 50% reduction from baseline] 2 3. Combined ezetimibe (10mg) and simvastatin(40 mg) decreased LDL- C by 50% and ischemic cardiovascular event(ice) risk by 22% compared to placebo 3 1. Okada, et al. Circ J. 2011;75: , 2. Reiner Z et al. Eur Heart J. 2011;32: , 3. Holme Am J Cardiol 2010;

63 STAR VYTORIN STrong, safe, Rapid on target

64 MSD does not recommend the use of any product in any different manner than as described in the approved Prescribing information. Physicians are advised to consult the prescribing information issued by the manufacturers before prescribing any drug discussed or described at this meeting.

65 VYTORIN Prescription Information 바이토린정 ( 에제티미브 / 심바스타틴 ) 10/10, 10/20, 10/40, 10/80 mg [ 효능효과 ] 원발성고콜레스테롤혈증 ( 이형접합가족형및비가족형 ) 및혼합형고지혈증환자의상승된총콜레스테롤 (total-c), LDL- 콜레스테롤 (LDL-C), 아포 B 단백 (Apo B) 및트리글리세라이드 (TG) 을감소시키고, HDL- 콜레스테롤 (HDL-C) 을증가시키기위한식이요법의보조제로서투여합니다. 동형접합가족형고콜레스테롤혈증 (HoFH) 환자의상승된총콜레스테롤및 LDL- 콜레스테롤을감소시키기위한다른지질저하치료 ( 예, LDL Apheresis) 의보조제로서, 또는다른지질저하치료가유용하지않은경우투여합니다. [ 용법용량 ] 바이토린을투여전및투여중인환자는표준콜레스테롤저하식을해야하며, 투여량은환자의 LDL- 콜레스테롤의기저치, 권장되는치료목표치및환자의반응에따라조절되어야합니다. 바이토린은식사와관계없이 1 일 1 회저녁에투여합니다. 일반적으로권장되는초회용량은 1 일 10/20mg 이고, LDL- 콜레스테롤감소의필요성이적은환자인경우 1 일 10/10mg 으로시작할수있습니다. 바이토린의투여를시작후또는용량적정후, 4 주이상의간격을두고혈중지질치를확인한후용량을조절합니다. 심바스타틴 80 mg 용량은저용량및다른스타틴계약물에비해근육병증의위험이높기때문에 10/80mg 용량은중증의고콜레스테롤혈증환자및심혈관계합병증의위험이높은환자중저용량에서치료목표에이르지못하고, 약물사용의유익성이잠재적인위험성을상회하는경우에한하여제한적으로투여합니다. 경증의신장애 ( 추정사구체여과율 (GFR) 60mL/min/1.73 m2 ) 환자의경우용량조절이필요하지않습니다. 만성신장질환을동반하고추정사구체여과율 <60mL/min/1.73 m2인환자의경우, 바이토린 10/20mg 을 1 일 1 회저녁에투여합니다. 이러한환자에게더높은용량으로투여할때에는신중히투여하여야하며세심히모니터링해야합니다. 경증의간장애환자의경우용량조절이필요하지않으나, 중등도또는중증의간장애환자의경우바이토린의투여가권장되지않습니다. [ 금기 ] 바이토린의성분에과민증인환자 / 활동성간질환환자또는혈청아미노전이효소수치가원인불명으로지속적으로높은환자 / 임부및수유부 / 강력한 CYP3A4 억제제를투여중인환자 / 겜피브로질, 사이클로스포린또는다나졸을투여중인환자 / 갈락토오스불내성 (galactose intolerance), Lapp 유당분해효소결핍증 (Lapp lactase deficiency) 또는포도당 - 갈락토오스흡수장애 (glucose-galactose malabsorption) 등의유전적인문제가있는환자

66 VYTORIN Prescription Information [ 경고 ] 1) 근육병증 / 횡문근융해 : 근육병증 / 횡문근융해의위험성은심바스타틴용량과관련이있습니다. 바이토린의투여를시작하는모든환자, 또는용량을증량한모든환자에게근육병증의위험성을알려야하며설명되지않는근육통, 압통또는근육약화가생기면즉시의사에게보고해야합니다. 만일근육병증이진단되거나의심되면, 바이토린의투여를즉시중지해야합니다. 근육병증을유발하는요소로는 65 세이상의고령자, 여성, 조절되지않는갑상선기능저하와신기능손상등이있습니다. 심바스타틴을투여한 41,413 환자의임상시험테이터베이스중평균추적조사기간 4 년이상인 24,747 명의환자 ( 약 60%) 에서, 심바스타틴 20mg, 40mg, 80mg/ 일을투여하였을때근육병증의발현율은각각약 0.03%, 0.08% 및 0.61% 였습니다. 이임상시험들에서환자는주의깊게모니터링되었으며, 약물상호작용이있는몇몇의약품들은제외되었습니다. 심근경색증의병력을가진환자에게심바스타틴 80mg/ 일을투여한임상시험에서 ( 평균 6.7 년동안추적조사 ) 근육병증발현율이 20mg 투여군에서 0.02% 인것에비해, 80mg 투여군에서는약 0.9% 였습니다. 근육병증의위험성은유사한 LDL- 콜레스테롤감소효능을가진다른스타틴계약물치료에비해심바스타틴 80mg 을복용하는환자군에서더높았습니다. 따라서바이토린 10/80mg 용량은심혈관계합병증의위험성이높은환자중저용량에서치료목표에이르지못하고, 약물사용의유익성이잠재적인위험성을상회하는경우에한하여제한적으로투여합니다. 바이토린 10/80mg 을복용하는환자가바이토린과상호작용하는약물을복용해야하는경우, 저용량의심바스타틴을함유한이약또는약물상호작용가능성이보다낮은다른스타틴 - 에제티미브요법을투여해야합니다. 다음약과의병용투여시근육병증 / 횡문근융해의위험성이증가됩니다 : - 바이토린의용량은아미오다론, 베라파밀또는딜티아젬을병용투여하고있는환자에서 1 일 10/20mg 을초과해서는안됩니다. 또한, 암로디핀을병용투여하고있는환자에서 1 일 10/40mg 을초과해서는안됩니다. - 바이토린과 CYP3A4 에대한중간정도의억제효과를가지는것으로알려져있는약물을병용투여하는경우, 근육병증의위험성이증가할수있습니다. - 바이토린은겜피브로질과병용투여하지않습니다. 바이토린과피브레이트계약물과의병용투여는피해야합니다. - 바이토린과푸시딘산을병용투여하는환자는주의깊게모니터링되어야하며, 바이토린의일시적인투여중단을고려할수있습니다. - 심바스타틴과지질저하용량 (1 일 1g 이상 ) 의니코틴산을병용투여하였을때근육병증 / 횡문근융해가관찰되었습니다. 바이토린과니코틴산병용투여시근육병증에대한위험성이증가할수있으므로, 1 일 10/20mg 을초과하는용량과지질저하용량 (1 일 1g 이상 ) 의니코틴산을병용투여하지않도록합니다.

67 VYTORIN Prescription Information 2) 간기능이상환자 : 3 개의위약대조, 12 주임상시험결과, 혈청아미노전이효소 (transaminase) 수치의지속적상승 ( 정상상한치의 3 배이상 ) 의발현율은바이토린을투여한전체환자에서 1.7% 였으나, 10/80mg 을투여한환자에서는 2.6% 로용량과관련있게나타났습니다. 바이토린을투여전및투여시작후임상적으로필요한시기에간기능검사를실시하는것이바람직합니다. 바이토린 10/80mg 으로증량한환자는증량하기전과증량하고 3 개월후, 이후치료의첫 1 년간주기적인 ( 예, 년 2 회 ) 간기능검사를추가실시합니다. 혈청아미노전이효소수치가상승된환자의경우간기능검사를다시하여모니터링하며, 정상치로돌아올때까지간기능검사를자주실시해야합니다. 만약, 혈청아미노전이효소 (ALT 또는 AST) 의수치가정상상한치의 3 배이상상승할경우바이토린의투여를중지하는것이바람직합니다. 바이토린을투여하는동안임상적증상및 / 또는고빌리루빈혈증을동반한심각한간손상이나황달이나타날경우, 즉각투여를중단합니다. 다른병인이확인되지않을경우, 바이토린을재투여하지않습니다. [ 이상반응 ] 바이토린 ( 또는바이토린과동등한에제티미브와심바스타틴의병용투여 ) 에대한안전성은임상시험에참여한 10,189 명이상의환자에서평가되었습니다. 바이토린은일반적으로내약성이우수하였습니다. 유사하게실시된 3 개의위약대조임상시험 (n=1,420) 에서투여약과의관련성을고려하지않고바이토린을투여한환자의 2% 이상에서보고되었으며, 위약군에서의발현율보다높은비율로보고된임상적이상반응은두통, 설사, 인플루엔자, 상기도감염, 근육통사지통이었습니다. [ 임부 / 수유부에대한투여 ] 임부에게투여해서는안되며, 임신이확인되면즉시투여를중지해야합니다. [ 소아에대한투여 ] 소아환자에대한안전성및유효성자료는불충분합니다. [ 고령자에대한투여 ] 임상시험에서, 바이토린을투여한환자중 792 명이 65 세이상이었고 (176 명의환자는 75 세이상이였음 ) 안전성은고령자환자와젊은환자간에유사하였으나, 일부고령자환자에서보다민감한반응이나타날수있음을배제할수없습니다. 개정년월일 2012 년 9 월 18 일 처방하시기전에각항목에대한자세한내용은제품설명서전문을참조하시기바랍니다.

68

69 1. Proctor, John C.L. Mamo. Arterioscler Thromb Vasc Biol. 2003;23: Visual Comparison of the retention of LDL (red) and Chylomicron remnants (yellow) in carotid arteries from normalrabbits and WHHL rabbits Using 3D confocal microscopy to quantitatively determine arterial retention of ApoB 100 and ApoB48 lipoprotein Watanabe Heritable HyperLipidemic strain is primary model of human familial hypercholesterolemia. WHHL rabbits have mutation in the gene that encodes the ApoB100/ApoE LDLreceptor The arterial retention of cholesterol derived from apob48 and apob100 lipoproteins was investigated in a rabbit carotid perfusion model under physiological conditions. We found that the intimal retention of cholesterol derived from apob48 lipoproteins was greater in WHHRs compared with controls despite evidence that up to 90% of apob48 lipoprotein internalization is mediated via the LDL receptor Normal rabbits WHHL rabbits WHHL rabbits = watanabe heritable hyperlipidemic rabbits

70 Ezetimibe/statin reduced migration of macrophage Immunolocalization of monocyte chemoattractant protein-1 (MCP-1) lipid diet (-) (+) E S E/S 1. Gómez-Garre British Journal of Pharmacology 2009;

71 Ezetimibe/statin might improves plaque stabilization (in rabbit model) Arms : ezetimibe, simvastatin, E/S Duration : 6 weeks Animal model : 34 Rabbits of accelerated atherosclerosis 13% 27% Femoral arteries 28% Normal lipid diet (-) (+) E normolipidemic diet (ND, B), untreated (C), ezetimibe-treated (Eze, D), simvastatin-treated (Simva, E) and ezetimibe + simvastatin-treated (Eze + Simva, F) rabbits. *p < 0.05 versus untreated rabbits. S E/S 1. Gómez-Garre British Journal of Pharmacology 2009;

72 Endothelial function marker was related with LDL-C lowering Arms : Simvastatin 80mg vs. Ezitimibe/Simvastatin(E/S) 10/10mg Duration : 6 wks Pts: 39 T2DM or IGT pts Absolute changes in FMD 1. Settergren European Heart Journal 2008;

73 ESC/EAS 2011 Guidelines: Management of Dyslipidemia in Diabetes 1 Type 1 Diabetes In all patients with type 1 diabetes and in the presence of microalbuminuria and renal disease, LDL-C lowering ( 30%) with statins as the first choice is recommended irrespective of the basal LDL-C concentration [Class I, Level C] Type 2 Diabetes In patients with type 2 diabetes and CVD or CKD, and in those without CVD who are over the age of 40 years with 1 or more CVD risk factors or markers of target organ damage, the recommended goal for LDL-C is <1.8 mmol/l (~70 mg/dl) and the secondary goal for non-hdl-c is <2.6 mmol/l (100 mg/dl) and for apo B is <80 mg/dl [Class I, Level B] In all people with type 2 diabetes, LDL-C goal <2.5 mmol/l (~100 mg/dl) is the primary target. Non-HDL-C <3.3 mmol/l (130 mg/dl) and apo B <100 mg/dl are the secondary targets. [Class I, Level B] Class= Class of recommendation, Level= Level of evidence, CV= cardiovascular, ESC/EAS = European Society of Cardiology/European Atherosclerosis Society. 1. Reiner Z et al. Eur Heart J. 2011;32:

74 Mean percent change from baseline at 6 weeks (%) VYTORIN 10/20mg provided 50% LDL-C reduction in Type 2 Diabetes patients 1 In a clinical study of patients with hypercholesterolemia and type 2 DM (VYTAL study) # # LDL-C TC HDL-C TG non-hdl-c hs-crp 20% 8% 10% 0% -10% -20% -30% -40% -50% -60% -54% -45% P< % -33% P<0.001 P= % -26% -26% -48% -41% P< % -14% VYTORIN 10/20mg (n=238) Atorvastatin 20mg (n=240) HDL-C: high-density lipoprotein cholesterol, hs-crp: high-sensitivity C-reactive protein, LDL-C: low-density lipoprotein cholesterol, TC: total cholesterol, TG: triglycerides #: median 1. Goldberg RB, et al. Mayo Clin Proc. 2006;81(12):

75 In hypercholesterolemia with Metabolic syndrome patients VYTORIN 10/20mg provided 50% reduction in LDL-C 1 In a clinical study of patients with hypercholesterolemia and Metabolic Syndrome (VYMET study) HDL-C= high-density lipoprotein cholesterol; hs-crp= high-sensitivity C-reactive protein; LDL-C: low-density lipoprotein cholesterol; TC= total cholesterol; TG= triglycerides. Number of patients 220 for E/S 20 mg, 216 for A 20 mg. Number of patients 216 for A 20 mg. 1. Robinson JG, et al. Am J Cardiol 2009;103:

76 Mean percent change from baseline (%) VYTORIN 10/20mg: Greater improvements in key parameters than mono statin in elderly hyperlipidemia patients In a clinical study of hypercholesterolemia patients 65 years of age with or without cardiovascular disease (VYTELD study) LDL-C TC HDL-C TG # non-hdl-c hs-crp * P< P< P< P<0.001 VYTORIN 10/20mg (n=232) Atorvastatin 20mg (n=238) HDL-C: high-density lipoprotein cholesterol, hs-crp: high-sensitivity C-reactive protein, LDL-C: low-density lipoprotein cholesterol, TC: total cholesterol, TG: triglycerides #: Nonparametric results (medians) are presented for triglycerides *: Longitudinal data analysis results are presented for high-sensitivity C-reactive protein. Foody JM, et al, Am J Cardiol 2010;106:

77 VYTORIN was Generally Well Tolerated 1 All VYTORIN 10/20, 10/40mg/day (n=513) All atorvastatin 10, 20, 40mg/day (n=771) Adverse Events 1 Clinical event 28.3% 24.6% Drug-related clinical event 4.1% 4.3% Discontinuation due to drug-related clinical event 1.9% 1.2% ALT or AST 3 ULN (consecutive) 0.8% 0.5% CK 10 X ULN with muscle symptoms 0% 0% ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; CK=creatine kinase. 1. Foody JM, et al. Am J Cardiol 2010;106:

78 1. Reiner Z et al. Eur Heart J. 2011;32: Relationship of Atherosclerosis and Cardiovascular disease Cardiovascular disease (CVD) due to atherosclerosis of the arterial vessel wall and to thrombosis is the foremost cause of premature mortality and of disability-adjusted life years (DALYs). The management of dyslipidemias as an essential and integral part of CVD prevention. Dyslipidemias cover a broad spectrum of lipid abnormalities, some of which are of great importance in CVD prevention.

79 Relative CHD Risk Non HDL-C Is Superior to LDL-C in Predicting CHD Risk The Framingham Study 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 non HDL-C and risk for CHD occurred within every level of LDL-C Non HDL-C is a stronger predictor of CHD risk than LDL-C < LDL-C, mg/dl < Liu Am J Cardiol. 2006;

80 Non-HDL-C concentration is in positive correlation with CVD 1. Emerging Risk Factors Collaboration JAMA. 2009;302(18)

81 1. Grundy SM. Circulation 1997;95:1-4. Non HDL-C: Secondary target of therapy Non-HDL-C = TC HDL-C Apo B concentration represents total number of lipoprotein particles (LDL + IDL + VLDL + chylomicron) This may be called non-hdl cholesterol or atherogenic cholesterol If baseline triglycerides: 200 mg/dl, Non-HDL cholesterol: Secondary target of therapy

82 Proportional reduction in atherosclerotic event rate (95% CI) The LOWER, The BETTER : Cholesterol Treatment Trialists Mean LDL cholesterol difference between treatment groups (mg/dl) 1. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2010; 376:

83 Significantly Greater % Reductions in CRP Were Achieved With Eze/Simva Significantly Greater % Reductions in CRP Were Achieved With Eze/Simva Compared With Each Corresponding Dose of Simva Monotherapy *p<0.001 vs. corresponding dose of SIMVA **p<0.01 vs. corresponding dose of SIMVA ***p<0.001 vs. pooled SIMVA NS= not significant 1. Pearson T et al. Am J Cardiol 2007;99:

84 Lower LDL-C levels were correlated with reduced CV risk In a meta-analysis of more than 169,000 patients in 26 clinical trials with statins. There were 87,903 (52%) participants with preexisting CHD, 32,210 (19%) with a history of diabetes, and 25,920 (15%) with other vascular disease. 1 for every 39mg/dL (1.07mmol/L) reduction in LDL-C There was a 22% relative reduction in the incidence of any major vascular event (p<0.0001) 1 21% relative reduction in the incidence of ischemic stroke (p<0.0001) 1 1. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2010; 376:

85 1. NCEP ATP III. JAMA. 2001;285: NCEP ATP III: LDL-C goal value Risk High Moderately high Moderate Low LDL-c goal <100 <130 <130 <160 Medication start 130 ( : optional) ( : optional)

86 1. Cohen DE, Armstrong EJ. In: Principles of pharmacology: The pathophysiologic Basis of Drug Therapy. 2 nd ed. Philadelphiak PA:Lippincott, Williams & Wilkins; 2007: ; 2. Wang DQH. Annu Rev Physiol. 2007;69: Cholesterol homeostasis 33% Dietary chol Cholesterol Pool (Micelles) 67% Biliary chol Free Chol Bile Acids Acetyl CoA Chol Cholesterol Pool LDLR Hepatic Apo B-100 Peripheral Tissues NPC1L1 Remnant receptors CMR VLD L ldl Fecal sterols CM Intestinal Apo B- 48 Atheroma LDL Blood

87 1. NCEP Circulation. 2002; Wilson PW et al. Circulation. 1998;97: Hubert HB et al. Circulation. 1983;67: Biology of Atherosclerosis: Contributing Factors 1 3 Aging Dyslipidemia Atherogenic Diet High Blood Pressure Diabetes Atherogenic Lipoprotein Deposition & Inflammatory Infiltration Lack of Physical Activity Smoking Genetic Predisposition Obesity

88 Ezetimibe/Statin Showed Complementary Effects on Cholesterol Absorption and Production Production Marker:Total Cholesterol Ratio a Absorption Marker:Total Cholesterol Ratio b Statin had inverse effects on absorption and production Ezetimibe had opposite effects vs. simvastatin Ezetimibe/Statin had complementary effects a Cholesterol production markers: lathosterol and desmosterol; b Cholesterol absorption markers: sitosterol and campesterol. 1. Assmann G, et al. Curr Med Res Opin. 2008;24(1):

89 Inhibition of cholesterol absorption may lower LDL-C levels effectively LDL-C, low density lipoprotein; CAD, coronary artery disease ; ATV, atorvastatin; RSV, rosuvastatin; EZE, ezitimibe 1. Okada Okada, et al. Circ J. 2011;75: Object : To evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers n patients with CAD Arm : ATV 20mg/day, RSV 5mg/day, ATV 10mg/EZE 10mg, RSV 2.5mg/EZE 10mg Patients : 171 patients with CAD r=0.35, p<0.01 r=0.0004, p=1.0 Ezetimibe-plus-statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis markers. r=0.12, p=0.33 r=0.13, p=0.27 Campesterol/TC ratio: an index of cholesterol absorption; Lathosterol/TC ratio: an index of cholesterol synthesis

90 Serum apob48 level might be a good marker for the detection of early atherosclerosis with normal-range levels of BP and TG Objective: To investigate the correlations between profiles of apob48-containing lipoproteins and the progression of atherosclerosis in subjects with normal TG levels Patients: 164 osaka police hospital (annual health check) Conclusion: The accumulation of CMR might be an independent risk factor for the development of atherosclerosis among subjects with TG levels between 100 mg/dl-150 mg/dl. The measurement of fasting apob48 level is very useful for the detection of early onset of atherosclerotic plaques BP blood pressure; TG, tryglyceride;cmr, chylomicron remnants 1. Nakatani, et al. Atherosclerosis 2011;218:

91 In patients not using statin, The surrogate atherosclerosis marker IMT correlated best with apob48 Objective : To investigate whether fasting plasma levels of apob48 can help to differentiate subjects with different conditions with remnant accumulation [e.g. FCH, T2DM and CAD] from subjects without remnant accumulation. The relationship between apob48 and IMT was also investigated Method : Patients-189 subject(fch, FH, CAD, T2DM, Control, CAD+T2DM) Conclusion : ApoB48 concentrations are highest in patients with FCH and in atherosclerotic subjects with T2DM. In patients not using statins, the surrogate atherosclerosis marker IMT correlates best with apob48, suggesting that fasting apob48 may help to detect subjects at risk. T2DM, type 2 diabetes mellitus; FCH, familial combined hyperlipidaemia ; FH, familial hypercholesterolaemia ; CAD, coronary artery disease ; IMT, Intima-media thickness 1. Alipour et al. Eur J Clin Invest 2012;42: