1. Dyslipidemia and Cardiovascular disease prevention 여수제일병원 이 우 석

2. 2016 년 우리나라 사망원인 〮 〮 〮 악성 신생물 심장 질환 + 뇌혈관 질환 그 외 원인 우리 나라 사람 2 명중 1 명은 암 또는 심 / 뇌혈관 질환으로 숨진다.

3. Cardiac Stress Tests Limitations: Requires a high level of blockage in one or more coronary arteries for abnormal result. Most heart attacks occur in vessels without significant blockage, or stenosis. What is the solution? Or, is there any?

4. Detect Your Plaques Earlier StagesEarlyModerateAdvancedLate ObstructionNone20%50%70% SymptomsNonenoneNoneYes Stress testNormal Abnormal Cardiac CTNoneAbnormal abnormal

5. Asia: Increasing cholesterol levels leading to CVD epidemic Hata J, et al. Circ J. 2013;77:1923-32 Male: 2.8% to 25.8% Female: 6.6% to 41.6% Multivariable-adjusted HRs (95% Cis) per 1mmol/L (39mg/dL) increase in cholesterol 1.2 (1.16-1.24) for ischemic stroke 0.91 (0.87-0.95) for hemorrhagic stroke 1.48 (1.43-1.53) for MI positively associated with the development of ischemic stroke and MI

6. Current Cholesterol Control in Korea 국민건강영양조사 2010-2012 “controlled” – LDL-C < 160 mg/dL, TG < 200mg/dL, HDL-C ≥ 40mg/dL

7. Cholesterol Lowering & Mortality - Meta-analysis of 26 randomized trials - LDL-C 39mg/dL CHD 20% Vasc. Death 14% Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-81

8. Combined effect of reductions in CV risk factors - Meta-anaylsis of 61 prospective, observational studies - SBP 10% T.Chol 10% CVD 45% Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-81

9. Primary Prevention 25 Primary Prevention Secondary Prevention Statin Trials: LDL-C Levels vs. Events (CHD) LDL-C achieved mg/dL (mmol/L) WOSCOPS – Pl AFCAPS - Pl AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Pl LIPID - Rx 4S - Pl CARE - Rx LIPID - Pl CARE - Pl HPS - Rx 0 5 10 15 20 25 30 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Event rate (%) 6 Secondary Prevention Primary Prevention Rx- Statin therapy Pl- Placebo Pra- pravastatin Atv- atorvastatin Sim- simvastatin 200 (5.2) PROVE-IT - Pra PROVE-IT – Atv TNT – Atv10 TNT – Atv80 IDEAL-Sim IDEAL-Atv ASCOT-PL MEGA-Rx MEGA-Pl JUPITER-Pl JUPITER-Rosu LaRosa JC, et al. N Engl J Med 2005;352:1425-35

10. GISSI 0-10-20 0.7 0.9 1.1 Relative risk of stroke in active versus control groups (non-log scale) Between-group difference in LDL cholesterol reduction (%; active minus control groups) -15 -25-35 -30 -40-45-55 -50 0 0.5 0.8 1.0 1.2 0.6 0.4 Post-CABG PROVE-IT PROSPER TNT A to Z MEGA ALLIANCE SEARCH ALLHAT-LLT IDEAL LIPID WOSCOPS AFCAPS-TexCAPS ASPEN HPS CARE SSSS ASCOT-LLA CARDS JUPITER GREACE MIRACL SPARC L SPARCL-CS (-) SPARCL-CS (+) Statin Trials: LDL-C Reduction and Stroke Amarenco P, et al. Lancet Neurol 2009;8:453-63

12. Fail to Achieve LDL-C Goals The ACCESS Study At week 54, n=2543 CHD patients Ballantyne CM et al. Am J Cardiol 2001;88:265-69

13. 100 80 60 40 20 0 Residual Major Coronary Events (%) Majority of Residual Risk for Cardiovascular Events Remains Despite LDL Lowering Therapy - The forgotten majority: unfinished business in cardiovascular risk reduction - © 2014 Boston Heart Diagnostics Corporation 13 AFCAPS/TexCAPS 6,605 4S 4,444 LIPID 9,014 CARE 4,159 WOSCOPS 6,595 Trial N HPS 20,536 Secondary Prevention Primary Prevention High Risk 62%75% 73%69%62% -38%-25% -27%-31%-38% Reduction in Major Coronary Events (%) [-100 ] [-80] [-60] [-40] [-20] 0 Libby P. J Am Coll Cardiol 2005;46:1225-28

14.  2013 ACC/AHA Guideline  2016 ESC/EAS Guidelines  HOPE-3 trial

15. History of Dyslipidemia Guideline Development :based on evidence 19881993200120042013 ATP I 1 Exclusive focus o n LDL-C ATP II 2 Risk assessment guides therapy ATP III 3 Lower LDL-C thr eshold for thera py initiation in hi gh risk patients ATP III Update 4 Lower LDL-C thr eshold for thera py initiation in v ery high risk pati ents ACC/AHA Guid elines 5 Use of moderate - or high-intensit y statin therapy f or patients acros s 4 major groups at risk for ASCVD * *ASCVD, Atherosclerotic Cardiovascular Disease 1. NCEP. Arch Intern Med.1988;148:36-69. 2. NCEP ATP II. Circulation.1994;89:1333-445. 3. NCEP ATP III. Circulation. 2002;106:3143. 4. Grundy SM, et al. Circulation. 2004;110:227-239.. 5. Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://cont ent.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

16. Keep it Simple: Start the Statin or Not? The systematic review of evidence from the highest quality RCTs with ASCVD outcomes identified strong evidence to indicate who should get which therapy at what intensity.

17. In summary  To Stain or Not to Statin (4 statin benefit groups)  Abandon LDL-C target  Web-based Global Risk Assessment – 10-year ASCVD risk  Nonstatin therapies (Fibrate, Niacin, Omega-3 fatty acids) – not provide acceptable ASCVD risk reduction Vaccine for pancreatitis !

18. Focus on ASCVD Risk Reduction: 4 statin benefit groups : Moderate- or high-intensity statin therapy recommended for these 4 groups Group 1 Clinical ASCVD CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin Group 3 Diabetes mellitus + age of 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L) Group 4 ASCVD risk ≥7.5% No diabetes + age of 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L) Group 2 LDL-C ≥190 mg/dL (~5 mmol/L) Trials: TNT IDEAL PROVE-IT SPARCL Trials: None Trials: CARDS TNT* HPS* Trials: ASCOT-LLA HPS JUPITER * Subgroup analysis

19. High Risk CHD and CHD Risk Equivalents; 10-year risk >20% 100 70 70 130 160 LDL LDL Goal Goal 130 160 190 Non-HDL Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Revised NCEP ATP III guideline : Reduction Goals for LDL and Non-HDL 0-1 Risk Factor  2 Risk Factors; 10-year risk  20% Medium Risk Low Risk

20. Risk Assessment in Primary Prevention http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/ Predict stroke & CHD events To guide initiation of statin Tx

21. Recommendations for statin therapy for ASCVD prevention ASCVD = Atherosclerotic cardiovascular disease

22.  Based on a comprehensive set of data from RCTs  Identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention.

24. The major 2 fundamental criticisms  Replacement of the “LDL target strategy” with the “fixed dose statin strategy” is clinically unwise  Crucial knowledge about atherogenesis is ignored (Misses Opportunities to Identify & Modify CAD)

25. The 1 st Criticism: Replacing the “LDL Target Strategy” with the “Fixed Statin Dose” Starategy Radomized trials of statins, 5 years durations Regression line indicates that there is NO atherosclerosis progression at LDL- C < 67 mg/dL Regression line indicates that there is No event at LDL-C of 57 mg/dl O’Keefe J, et al. J Am Coll Cariol 2004;43:2142-6

26. Proprietary and Confidential © AstraZeneca 2013 FOR INTERNAL USE ONLY This document is not to be shared or distributed outside AstraZeneca

28. 2 ND Criticism: Ignores basic data about atherogenesis Vietnam:105 soldiers (avg age 22) : 45% had plaque; 5% had severe CAD Calcium scan is positive in 40-60% by age 45 In Bogalusa Heart study, at 30 yr follow up, risk factors can be ‘tracked’ into middle age In ARIC study, intensive modification of LDL levels in PCSK mutant population was associated with 60% reduction of CV events. High lifetime risk can be identified and modified in Youth

29. Shrinkage of the “Intermediate Risk” group

30. Proprietary and Confidential © AstraZeneca 2013 FOR INTERNAL USE ONLY This document is not to be shared or distributed outside AstraZeneca

31. Another new ESC lipid guidelines

32. Total Cardiovascular Risk Estimation Systemic Coronary Risk Estimation (SCORE) System CV risk : the likelihood of a person developing a fatal or non-fatal atherosclerotic CV event o ver a defined period of time

33. SCORE chart (high CVD vs. low CVD) <225/100,000 in men, <175/100,000 in women≥450/100,000 in men, ≥ 350/100,000 in women

34. Automatically very high or high CV risk Persons with Documented CVD Type 1 or type 2 DM Very high levels of individual risk factors Chronic kidney disease

35. 4 Risk categories Very high-riskSubjects with any of the following: Documented CVD, clinical or unequivocal on imaging. Documented CVD includes previous MI, ACS, coronary revascularization (PCI, CABG) and other arterial revascularization procedures, stroke and TIA, and PAD. Unequivocallyl documented CVD on imaging is what has been shown to be strongly predisposed to clinical events, such as significant plaque on coronary angiography or carotid ultrasound. DM with target organ damage such as proterinuria or with a major risk factor such as smoking, hypertension or dyslipidemia. Severe CKD (GFR < 30mL/min/1.73 m 2 ) A calculated SCORE≥10% for 10-year risk of fatal CVD. High-riskSubjects with : Markedly elevated single risk factors, in particular cholesterol >8mmol/L (>310mg/dL) (e.g., in familial hypercholesterolaemia) or BP ≥180/110 mmHg. Most other people with DM (some young people with type I diabetes may be at low or moderate risk). Moderate CKD (GFR 30-59 mL/min/1.73m 2 ). A calculated SCORE≥5% and <10% for 10-year risk of fatal CVD. Moderate-riskSCORE is ≥1% and <5% for 10-year risk of fatal CVD. Low-riskSCORE <1% for 10-year risk of fatal CVD.

36. Recommendations for treatment targets for LDL-C In patients at VERY HIGH CV risk (established CVD, type 2 diabetes, type I diabetes with target organ damage, moderate to severe CKD or a SCORE level ≥10%) the LDL-C goal is <1.8 mmol/L (less than ~70 mg/dL) and/or ≥50% LDL-C reduction when target level cannot be reached. In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level ≥5 to <10%) an LDL-C goal <2.5mmol/L (less than ~100mg/dL) should be considered. In subjects at MODERATE risk (SCORE level >1 to ≤5%) an LDL-C goal <3.0 mmol/L (less than ~115 mg/dL) should be considered. IA IIaA IIaC

37. Intervention strategies as a function of total CV risk and LDL-C level

38. Continental Divide on Lipid Guidelines The U.S. guidelines recommend giving a statin to all high-risk patients, even those with low cholesterol, but the ESC/EAS guidelines do not do that (no tx if low LDL despite high risk). While the ACC/AHA guidelines do not specify a numeric goal, the ESC/EAS guidelines set a target of a reduction in LDL. Fasting is no longer required before screening for lipid levels in Europe due to “new evidence that non-fasting blood samples give similar results for cholesterol.” However, fasting is recommend in the U.S. the guidelines.