血脂治療新趨勢 (hsupc) 2015 by ksdoctor

血脂治療新趨勢 Where do we stand in 2015

高醫心臟血管內科許栢超醫師 / 助理教授 Po-Chao Hsu, MD, PHD 2015/11/13 醫師公會

Topic outline  Association between atherosclerosis and dyslipidemia  Lipid metabolism  Current lipid guideline of world and health insurance in

Taiwan  Drug therapy for dyslipidemia  What is new in recent years?  LDL-lowering therapy-related news  IMPROVE-IT study and associated study  How about PCSK9 inhibitor?

 Take Home Message

Atherothrombosis: A Generalized and Progressive Process Thrombosis Unstable angina MI

ACS

Ischemic stroke/TIA Critical leg ischemia

Atherosclerosis

Intermitent claudication CV death

Stable angina/ Intermittent claudication Circulation. 2001;104:365-72

Lancet 2013; 381: 1211â&#x20AC;&#x201C;22

Importance of Cholesterol in Atherosclerosis

N Engl J Med. 1997;337:408â&#x20AC;&#x201C;416.

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk

1% decrease in LDL-C reduces CHD risk by 1%

6 Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1% increase in HDL-C reduces CHD risk by 3%

CHD Risk Increases as Plasma Cholesterol Increases MRFIT (n=356,222) 1

Framingham Study (n=5,209) 2

150

125

100

10 CHD Mortality 8 Rate per 1,000 6

CHD Incidence per 75 1,000 50

0 100

150

200

250

Serum Cholesterol, mg/dL

300

<204

205–234

235–264 265–294

Serum Cholesterol, mg/dL

CHD = coronary heart disease; MRFIT = Multiple Risk Factor Intervention Trial. 1. Stamler J et al. JAMA. 1986;256:2823–2828. 2. Reprinted from Am J Med, Vol 76, WP Castelli, Epidemiology of coronary heart disease: the Framingham Study, pp. 4–12, Copyright 1984, with permission from Excerpta Medica Inc.

>295

Stabilization of ‘vulnerable’ plaques by lipid lowering Non-atherosclerotic coronary artery Physiological intima

“Vulnerable” plaque

“Stable” plaque

Collagen-poor, thin fibrous cap Large lipid pool, Few SMCs Many macrophages (MMP, TF, PAI-1)

Thick fibrous cap, Smaller lipid pool Few macrophages, Collagen-rich

Lumen

Intima Media Adventitia

Stabilization Qualitative/functional changes

Regression Masanori Aikawa and Peter Libby European Heart Journal, 2001 Peter Libby and Masanori Aikawa Nature Medicine, 2002

Quantitative changes

Relation Between CHD Events and LDL Cholesterol in Statin Trials PI = Placebo Rx = Treatment

Primary Prevention

% of Paients with CHD Event

Secondary Prevention 4S-PI

25 TNT-Entry

20 4S-Rx 15

LIPID-PI CARE-PI

CARE-Rx

LIPID-Rx

TNT

WOS-PI

WOS-Rx

AFCAPS-Rx AFCAPS-PI

0 50

110

130

150

170

190

210

LDL Cholesterol (mg/dL) AFCAPS: Lovastatin; 4S: Simvastatin WOS, LIPID, CARE: Pravastatin

Kastelein. Atherosclerosis 1999;143:S17-S21

Relationship between LDL-C levels and change in percent atheroma volume for several IVUS trials 1.8

REVERSAL

R2 = 0.97 P<0.001

pravastatin

CAMELOT placebo

1.2 Median change in Percent Atheroma Volume (%)

0.6

REVERSAL atorvastatin

A-Plus

Progression

placebo

Regression -0.6

ASTEROID -1.2

rosuvastatin

80 100 90 Mean LDL-C (mg/dL)

110

Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

120

Side effects

LDL reduction

LDL-reduction and side effects with increasing doses of statins

Leitersdorff et al. Europ. Heart J. 2001

Inhib. of synthesis

Dual Inhibition

Ezetimibe alone

Statin alone

Ezetimibe/Statin

CHANGE OF SYNTHESIS AND ABSORPTION MARKERS1

Inhib. of absorption

absorption synthesis

MEAN LDL-C LOWERING2,3

10%

LDL-C

synthesis

synthesis absorption absorption

LDL-C

20% 30% 40% 50%

LDL-C

STATIN

20% 30-45%

EZETIMIBE

As high as

60% Fer

Association between the Presence of Inactivating Mutations in NPC1L1, LDL-cholesterol, and CHD

OR 0.47 (0.25-0.87)

0.4 0.6 1.0 1.4 1.8 Odds ratio for CHD in mutation carriers

Stitziel NO et al. NEJM 2014 Fe-po

Consistent Effect Per Unit Lower LDL-C on Risk of CHD • •

Comparison of polymorphisms in genes that lower LDL-C through common final pathway of LDL receptor (including PCSK9) adjusted per unit lower LDL-C Up to 63,746 cases of CHD and 130,681 control subjects

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

http://www.CARDIOGRAMPLUSC4D. org

Effect of LDL-cholesterol on CHD risk is independent of mechanism

Ference et al. AHA abstract presentation 2014

The Study of Heart and Renal Protection (SHARP) (Eze + Simva in patients with chronic kidney disease; n=9270)

Proportion suffering event (%)

Risk ratio 0.83 (0.74 – 0.94) Logrank 2P=0.0022

Placebo

Eze/simv 10

5 0 0

2 3 Years of follow-up

5 Lancet 2011 (377): 2181–2192

LDL-cholesterol and reduction in cardio-vascular events

SHARP

Holme I et al. Am J Cardiol 2010;105:1802â&#x20AC;&#x201C;1808 Imp

Lipid metabolism

Current lipid guideline of world and health insurance in Taiwan

Evolution of NHLBI Supported Guidelines

NCEP ATP I 1988

NCEP ATP II 1993

NCEP ATP III 2001

Updated NCEP ATP III 2004

AHA/ACC Update 2006

More Intensive Treatment Recommendations

Framingham MRFIT LRC-CPPT Coronary Drug Project Helsinki Heart CLAS

Angiographic trials (FATS, POSCH, SCOR, STARS, Ornish, MARS) Meta-analyses (Holme, Rossouw)

4S WOSCOPS CARE LIPID AFCAPS/ TexCAPS

NHLBI = National Heart, Lung, and Blood Institute. NCEP ATP = National Cholesterol Education Panel Adult Treatment Panel. AHA = American Heart Association. ACC = American College of Cardiology.

HPS PROVE-IT ASCOT-LLA PROSPER ALLHAT-LLT

TNT IDEAL

Intensive LDL-C Goals for High-Risk Patients

Recommended LDL-C treatment goals ATP III Update 20041

AHA/ACC guidelines for patients with CHD*,2

<100 mg/dL: Patients with CHD or CHD risk equivalents (10-year risk >20%)1

<100 mg/dL: Goal for all patients with CHD†,2

<70 mg/dL: Therapeutic option for very high-risk patients 1

<100 mg/dL

2006

Update

<70 mg/dL: A reasonable goal for all patients with CHD†,2

<70 mg/dL • If it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C─lowering therapy, including drug combinations.

* And other forms of atherosclerotic disease.2 † Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabol ic syndrome (triglycerides [TG] ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1 1. Grundy SM et al. Circulation. 2004;110:227–239. 2. Smith SC Jr et al. Circulation, 2006; 113:2363–2372.

ESC / EAS Guidelines LDL-C

< 70 mg/dl (< 1.8 mmol/l) or > 50% LDL-C reduction

LDL-C

< 100 mg/dl < 115 mg/dl (<2.5 mmol/l)

SCORE ≥ 10% Documented

CVD

DM + ≥ 1 RF

and/or Severe TOD*

LDL-C

SCORE 10 - 5% DM 0 RF

SCORE 5 - 1%

Markedly elevated Moderate RF

CKD

(< 30)

(30-60)

Very High Risk

(< 3 mmol/l)

High Risk

SCORE < 1%

Consider Drug if LDL > 190 mg/dL (> 4.9 mmol/L)

Moderate Risk

Low Risk

* TOD= target organ damage (such as microalbuminuria 30-300 mg/24h) Joint ESC Guidelines. Eur J Prev Cardiol 2012; 19: 585-667

ESC/EAS Guidelines. Eur Heart J 2011; 32: 1769-1818

2013 ACC / AHA Guidelines 4 Major Statin Benefit Groups

1. Clinical ASCVD (ACS or history of MI, stable or unstable angina, revascularisation, stroke, TIA, or PAD presumed to be of atherosclerotic origin)

2. LDL-C  190 mg/dL

3. Diabetes aged 40-75 y with LDL-C 70-189 mg/dL 4. Estimated 10-year ASCVD risk  7.5 % with LDL-C 70-189 mg/dL (and age 40-75 y)

2013 ACC/AHA Guideline: High-Moderate statin

Rosuvastatin 40mg is not indicated in Taiwan. Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

2013 ACC/AHA Guideline: Summary  此guideline的更新主要的根據是以RCT試驗的結果  藉由RCT試驗結果, 找出了四個最能得到statin好處的群組  可藉由新的ASCVD風險預測的程式來計算出十年或終生風險  生活型態的調整在ASCVD的風險降低上仍是非常的重要  沒有證據支持使用LDL或是non-HDL goal來作為血脂治療標準  Non-statin的藥物治療不管是單獨或是附加到statin使用, 都

無法獲得顯著ASCVD風險降低的好處  高強度statin治療是指可降低LDL≥ 50%,中強度statin治療則是指降低LDL 30-50%  Treat to target以及lower is best不再是治療的策略, 應該是以treat to ASCVD risk為現今治療的策略 CHD = coronary heart disease.

2014 National Lipid Association(NLA) guideline

J Clin Lipidol. 2014 Sep-Oct;8(5):473-88

2014 National Lipid Association(NLA) guideline

J Clin Lipidol. 2014 Sep-Oct;8(5):473-88

全民健康保險降膽固醇藥物給付規定

全民健康保險降血脂藥物給付規定表(新版)（102/8/1) 非藥物治療心血管疾病或與藥物治療可並行糖尿病患者

最主要的改變：

起始藥物治療血脂值

血脂目標值

TC≧160mg/dL或

TC＜160mg/dL或

LDL-C≧100mg/dL

LDL-C＜100mg/dL TC＜200mg/dL或

2個危險因子或以上

給藥前應有3-6個月非藥物治療

TC≧200mg/dL或

1個危險因子

給藥前應有3-6個月非藥物治療

TC≧240mg/dL或

處方規定第一年應每3-6個月抽血檢查一次，第二年以後應至少每 6-12個月抽血檢查一次，同時請注意副作用之產生如肝功能異常，橫紋肌溶解症。

LDL-C≧130mg/dL LDL-C＜130mg/dL 1. 心血管疾病或糖尿病患者，起始治療LDL-C由 TC＜240mg/dL或

LDL-C≧160mg/dL LDL-C＜160mg/dL 如以達治療目標得 ≧130mg/dl降為100mg/dl，目標＜100mg/dl 考慮減量至最低有給藥前應有3-6個月非藥物治療

效劑量,並持續治療之 (移除)

LDL-C≧190mg/dL LDL-C＜190mg/dL 2. 刪除達到治療目標需 “減量至最低有效劑量”

0個危險因子

全民健康保險降膽固醇藥物給付規定表 •心血管疾病定義： (一) 冠狀動脈粥狀硬化病人：心絞痛病人，有心導管證實或缺氧性心電圖變化或負荷性試驗陽性反應者(附檢查報告) (二) 缺血型腦血管疾病病人包含： 1.腦梗塞。2.暫時性腦缺血患者(TIA)。（診斷須由神經科醫師確立） 3.有症狀之頸動脈狹窄。（診斷須由神經科醫師確立） •危險因子定義： 1.高血壓 2.男性≧45歲，女性≧55歲或停經者 3.有早發性冠心病家族史(男性≦55歲，女性≦65歲) 4.HDL-C<40mg/dL 5.吸菸(因吸菸而符合起步治療準則之個案，若未戒菸而要求藥物治療，應以自費治療)。

Drug therapy for dyslipidemia

HMG Reductase

B-100 B-48

Drugs: Options Lipid profile

First Choice

Second Choice

LDL-C

Statin

Ezetimibe Resins

LDL and Triglycerdies

Statin

Fibrate or Niacin

LDL and Triglycerides

Statin

Statin + fibrate (Niacin ) Statin + omega3

Triglycerides and HDL-C

Fibrates or niacin

Triglycerides and LDL

Fibrates

History of Statins Fluvastatin Atorvastatin Rosuvastatin

Pravastatin B M Y

1991 1987

2000 1996 2003 1993 1997

Lovastatin

Cerivastatin

Simvastatin

2001/8 withdrawal

Potential time course of statin effect

www.lipidsonline.org

Not all statins are equal?

After the “standard” dose is reach, each doubling of dose decreases LDL by 6% ONLY

Statin Dose Titration  Monotherapy is the traditional approach

 Current practice based on up-titration of statin dose  “Rule of 6”  For every doubling of the statin dose, LDL-C is lowered

only by another 6% –6%

20 mg

Statin 10 mg

–6%

40 mg

–6%

80 mg

% Reduction in LDL-C Adapted from Grundy SM et al J Am Coll Cardiol 2004;43:2142–2146; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Circulation 2002;106:3143–3421; Knopp RH N Engl J Med 1999;341:498–509; Stein E Eur Heart J Suppl 2001;3(Suppl E):E11–E16.

Lipid Management Pharmacotherapy TC

LDL

HDL

Patient tolerability

 19-37%

 25-50%

4-12%

 14-29%

Good

 13%

18%

 9%

Good

Bile acid sequestrants

7-10%

10-18%

Nicotinic acid

 10-20%

14-35%

 30-70%

Reasonable to Poor

19%

4-21%

11-13%

30%

Good

Therapy Statins* Ezetimibe

Fibrates

Neutral or

Poor

HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol,TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin.

Crestor 10mg = atorva 40mg= simva 80mg Rosuvastatin 40mg is not indicated in Taiwan.

Safety of Intensive-Dose Statin Percentage changes in liver and muscle enzymes by percent LDL-C reduction1

Low dose, high potencyS80will be better A80

R40

Rosuvastatin (10, 20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg) Lovastatin (20, 40, 80 mg) Fluvastatin (20, 40, 80 mg) Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) Pravastatin (20, 40 mg)

S80 A80 R40 Reference:

1. Davidson MH, Expert Opin Drug Saf 2004; 3(6): 547-557. 2. Jones P et al. Am J Cardiol 2003; 92: 152-160.

Rosuvastatin 40mg is not indicated in Taiwan.

Ezetimibe Co-administered with Statins versus High-Dose Statins

Mean % change in LDL-C from baseline

Ezetimibe 10 mg Ezetimibe 10 mg Ezetimibe 10 mg Ezetimibe 10 mg + + + + Atorvastatin atorva Simvastatin simva Pravastatin prava Lovastatin lova 80 mg 10 mg 10 mg 80 mg 10 mg 10 mg 40 mg 40 mg (n=62) (n=66) (n=67) (n=65) (n=69) (n=73) (n=71) (n=64)

–20 –31

–40

–45 –54

–60

–53

–34

–30

–34

–46

10+10 ~ ~ 80

Ezetimibe 10 mg once daily together with the lowest statin dose reduced plasma LDL -C as much as or more than the highest dose tested of statin alone.

What is New in recent years? LDL lowering therapy-related News - LDL < 50 mg/dl? - Statin related new-onset diabetes 2. IMPROVE-IT study & associated study 3. How about PCSK9 inhibitor? 1.

All statin clinical outcome trials: Effects of baseline LDL-C Relative risk reduction in major vascular events per 40 mg/dL reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) 無論baseline LDL-C多少，只要降低LDL-C都有好處 Number of Events

Baseline LDL-C

Treatment-arm (n=84573)

Control-arm (n=84565)

Relative risk (95% CI)

< 80 mg/dL

910

1012

0.78 (0.61-0.99)

80-100 mg/dL

1528

1729

0.77 (0.67-0.89)

100-120 mg/dL

1866

2225

0.77 (0.70-0.85)

120-150 mg/dL

2007

2454

0.76 (0.70-0.82)

> 150 mg/dL

4508

5736

0.80 (0.76-0.83)

CTT Collaborators. Lancet. 2010; 376:1670-1681.

Change in LDL-C in the diabetic subgroup Results from the VOYAGER individual patient data meta-analysis

Change in LDL-C from baseline (LSM %)

5 mg

Dose (log scale) 10 mg 20 mg 40 mg

80 mg

-10 Simvastatin

-20

Atorvastatin

-27.4 (n=14)

-30 -40 -50

-40.0 (n=41)

-35.7 (n=2286) -45.2 (n=3373)

Rosuvastatin

-33.7 (n=827) -39.8 (n=173)

-41.8 (n=1455) -50.6 (n=1076)

-60 Rosuvastatin 10â&#x20AC;&#x2019;40 mg significantly superior to equal and double mg doses of atorvastatin and simvastatin (p<0.01)

Karlson BW et al. Nut Metab Cardiovasc Dis 2012; 22: 697â&#x20AC;&#x201C;703

-47.2 (n=32) -46.6 (n=356)

-55.5 (n=768)

-50.4 (n=602)

IS LOWER STILL BETTER IF LDL-C < 50 MG/DL? CV benefits

Safety

CV Benefit from JUPITER study LDL>50

LDL<50

24% 65%

J Am Coll Cardiol 2011;57:1666â&#x20AC;&#x201C;75)

Safety from JUPITER study

LDL-C<50 mg/dL 與LDL-C>50 mg/dL在肌肉、肝臟與腎臟安全性相似

J Am Coll Cardiol 2011;57:1666–75)

How about statin related new-onset DM? ď&#x192;źBenefit

ď&#x192;źRisk

Statins and risk of incident diabetes: a collaborative meta-analysis 63 65 66 55 62 73 76 58 59 59 Absolute risk: 4.89% vs 4.5% NNH: 255

66 67 Relative risk increase 9%

Lancet, Published Online February 17, 2010

DM +12%

CVD -16% When expressed absolute terms there was be 1 additional Low dose,inhigh potency will bettercase of diabetes for every 498 patients treated for 1 year compared with 1 fewer patient experiencing a cardiovascular event for every 155 patients treated for 1 year. JAMA 2011;305:2556-64

Statins and risk of incident diabetes: a collaborative meta-analysis 

one additional case of diabetes per 255 patients taking statin therapy for 4 years (12·23 cases per1000 patient-years with statin treatment and 11·25 cases per 1000 patientyears with control therapy).



Re reduction in major coronary events (coronary heart disease death and non-fatal myocardial infarction) of 5·4 events per 255 patients treated for 4 years compared with control therapy for a 1 mmol/L reduction in LDLcholesterol concentration.

Lancet 2010; 375: 735–42

Statin and NODM 健保資料庫分析

MACE

New onset diabetes

14.5%

In-hospital death 39%

Wang KL, .. Chiang CE. J Am Coll Cardiol 2012;60(14):1231-1238.

NODM from the JUPITER trial 無DM危險因子

一個以上DM危險因子 ↓52%

↓39%

↑ 28%

與安慰組相較…. 吃 crestor 組平均提早5·4 個星期診斷出糖尿病 Lancet 2012; 380: 565–71

好處>>壞處

N Engl J Med. 2015 Jun 3. [Epub ahead of print]

Background: Cholesterol Lowering ➢ Lowering LDL cholesterol (LDL-C) has been a mainstay

of cardiovascular prevention ➢ Evidence mostly from statin trials which show reduction

in morbidity and mortality – High-dose statins further reduce non-fatal CV events ➢ To date, no lipid-modifying therapy added to statins has

been demonstrated to provide a clinical benefit – Fibrates, niacin, CETP inhibitors ➢ Recent ACC/AHA Guidelines have emphasized use of

statin therapy ➢ Despite current therapies, patients remain at high risk

Ezetimibe: Background ➢ Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1)

protein – located primarily on the epithelial brush border of the GI tract – resulting in reduced cholesterol absorption ➢ When added to statin, produces ~20% further

reduction in LDL-C ➢ Two recent human genetic analyses have correlated

polymorphisms in NPC1L1 with lower levels of LDL-C and lower risk of CV events* *MI Genetics Consortium Investigators NEJM 2014; online Nov 12; Ference BA et al AHA 2014

Goals IMPROVE-IT: First large trial evaluating clinical efficacy of combination EZ/Simva vs. simvastatin (i.e., the addition of ezetimibe to statin therapy): ➢ Does lowering LDL-C with the non-statin agent

ezetimibe reduce cardiac events? ➢ “Is (Even) Lower (Even) Better?”

(estimated mean LDL-C ~50 vs. 65mg/dL) ➢ Safety of ezetimibe

Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Study Design Patients stabilized post ACS ≤ 10 days: LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx) N=18,144

*3.2mM **2.6mM

Standard Medical & Interventional Therapy

Simvastatin 40 mg

Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011)

Ezetimibe / Simvastatin 10 / 40 mg

Follow-up Visit Day 30, every 4 months

90% power to detect ~9% difference

Duration: Minimum 2 ½ -year follow-up (at least 5250 events)

Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Patient Population Inclusion Criteria: ➢ Hospitalization for STEMI, NSTEMI/UA < 10 days ➢ Age ≥ 50 years, and ≥ 1 high-risk feature:

– New ST chg, + troponin, DM, prior MI, PAD, cerebrovasc, prior CABG > 3 years, multivessel CAD ➢ LDL-C 50-125 mg/dL (50–100 mg/dL if prior lipid-lowering Rx)

Major Exclusion Criteria: ➢ CABG for treatment of qualifying ACS ➢ Current statin Rx more potent than simva 40mg ➢ Creat Cl < 30mL/min, active liver disease

Study Metrics Simva (N=9077)

EZ/Simva (N=9067)

Uptitration to Simva 80mg, %

Premature study drug D/C, %

Median follow-up, yrs

6.0

5.9

Withdraw consent w/o vital status, %/yr

0.6

Lost to follow-up, %/yr

0.10

0.09

Follow up for primary endpoint, %

Follow up for survival, %

Total primary endpoint events = 5314 Total patient-years clinical follow-up = 97,822 Total patient-years follow-up for survival = 104,135

Baseline Characteristics Simvastatin (N=9077) %

EZ/Simva (N=9067) %

Age (years)

Female

Diabetes

MI prior to index ACS

STEMI / NSTEMI / UA

29 / 47 / 24

Days post ACS to rand (IQR)

5 (3, 8)

Cath / PCI for ACS event

88 / 70

95 (79, 110)

95 (79,110)

Prior lipid Rx LDL-C at ACS event (mg/dL, IQR)

LDL-C and Lipid Changes 1 Yr Mean

LDL-C

HDL

hsCRP

Simva

69.9

145.1

137.1

48.1

3.8

EZ/Simva

53.2

125.8

120.4

48.7

3.3

Δ in mg/dL

-16.7

-19.3

-16.7

+0.6

-0.5

Median Time avg 69.5 vs. 53.7 mg/dL

Primary Endpoint — ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke HR 0.936 CI (0.887, 0.988) p=0.016

Simva — 34.7% 2742 events NNT= 50

EZ/Simva — 32.7% 2572 events

7-year event rates

N Engl J Med. 2015 Jun 3. [Epub ahead of print]

Primary and 3 Prespecified Secondary Endpoints — ITT Simva* EZ/Simva* p-value 0.936

Primary CVD/MI/UA/Cor Revasc/CVA

0.948

Secondary #1 All D/MI/UA/Cor Revasc/CVA

0.912

Secondary #2 CHD/MI/Urgent Cor Revasc

0.945

Secondary #3 CVD/MI/UA/All Revasc/CVA 0.8

1.0

Ezetimibe/Simva Better

1.1

Simva Better

34.7

32.7

0.016

40.3

38.7

0.034

18.9

17.5

0.016

36.2

34.5

0.035

*7-year event rates (%)

UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization (≥30 days after randomization); All D, all-cause death; CHD, coronary heart disease death; All Revasc, coronary and non-coronary revascularization (≥30 days)

Individual Cardiovascular Endpoints and CVD/MI/Stroke All-cause death

HR 0.99

CVD

1.00

6.8

6.9

0.997

CHD

0.96

5.8

5.7

0.499

0.87

14.8

13.1

0.002

Stroke

0.86

4.8

4.2

0.052

Ischemic stroke

0.79

4.1

3.4

0.008

Cor revasc â&#x2030;Ľ 30d

0.95

23.4

21.8

0.107

1.06

1.9

2.1

0.618

CVD/MI/stroke

0.90

22.2

20.4

0.003

0.6 Ezetimibe/Simva Better

1.0

1.4 Simva Better

Simva* EZ/Simva* p-value 15.3 15.4 0.782

*7-year event rates (%)

CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56

Simva — 22.2% 1704 events

EZ/Simva — 20.4% 1544 events

7-year event rates

Major Pre-specified Subgroups Simva† EZ/Simva† Male Female

34.9 34.0

33.3 31.0

Age < 65 years Age ≥ 65 years

30.8 39.9

29.9 36.4

No diabetes Diabetes

30.8 45.5

30.2 40.0

Prior LLT No prior LLT

43.4 30.0

40.7 28.6

LDL-C > 95 mg/dl LDL-C ≤ 95 mg/dl

31.2 38.4

29.6 36.0

0.7

1.0 Ezetimibe/Simva Better

1.3 Simva Better

†7-year

event rates

*p-interaction = 0.023, otherwise > 0.05

N Engl J Med. 2015 Jun 3. [Epub ahead of print]

Safety â&#x20AC;&#x201D; ITT No statistically significant differences in cancer or muscle- or gallbladder-related events Simva n=9077 %

EZ/Simva n=9067 %

ALT and/or ASTâ&#x2030;Ľ3x ULN

2.3

2.5

0.43

Cholecystectomy

1.5

0.96

Gallbladder-related AEs

3.5

3.1

0.10

Rhabdomyolysis*

0.2

0.1

0.37

Myopathy*

0.1

0.2

0.32

Rhabdo, myopathy, myalgia with CK elevation*

0.6

0.64

Cancer* (7-yr KM %)

10.2

0.57

* Adjudicated by Clinical Events Committee

% = n/N for the trial duration

Conclusions IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dL at 1 year)

YES: Confirms ezetimibe safety profile Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events

Results could be considered for future guidelines

A Naturally Randomized IMPROVE-IT Trial ONLINE FIRST 11 March 2015

Brian A. Ference, M.D., M.Phil., M.Sc., F.A.C.C. Division of Translational Research and Clinical Epidemiology (TRaCE) Division of Cardiovascular Medicine Wayne State University School of Medicine

Background • Lowering LDL-C by inhibiting HMGCR with a statin reduces the risk of CV events • Ezetimibe, an NPC1L1 inhibitor, ultimately lowers LDL-C by the same common final pathway as statins (up regulation of hepatic LDL-C receptors)

• IMPROVE-IT showed that lowering LDL-C by inhibiting NPC1L1 with ezetimibe also reduces the risk of CHD • However, considerable uncertainty persists as to the comparative effect of lower LDL-C on the risk of CHD mediated by inhibiting NPC1L1 and HMGCR

Objectives â&#x20AC;˘ Specifically, we compared the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins) or both (targets of combination therapy) on the risk of CHD using a novel 2x2 factorial Mendelian randomization study design Analogous to a 2x2 factorial randomized trial comparing the effect of treatment with ezetimibe, a statin or both on the risk of CHD NB: This study was conducted and reported PRIOR to IMPROVE-IT Results

Study Population • Study Sample: 108,376 subjects from 14 studies (dbGAP) • Exposure: random allocation to lower LDL-C mediated by the combined effect of polymorphisms in NPC1L1 and HMGCR genetic LDL-C scores, respectively • Outcome: 10,464 first CHD events (Coronary heart disease death or non-fatal MI) • External validation: up to 63,746 cases of CHD and 130,681 controls subjects in CARDIoGRAMplusC4D Consortium

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Mendelian Randomization Naturally Randomized Trial Eligible Population SNP associated with LDL-C (Naturally Random Allocation of Alleles)

Lower LDL-C Allele (Treatment Arm)

Other Allele (Usual Care Arm)

Randomized Controlled Trial Eligible Population LDL-C Lowering Therapy (Random Allocation of Treatment)

Usual Care Arm

Treatment Arm

Î&#x201D; LDL-C

Incident Major Cardiovascular Events

NPC1L1 and HMGCR Genetic LDL-C Scores • Sum of effect of LDL-C lowering alleles included in either score • Overcome weak effect of most NPC1L1 and HMGCR SNPs on LDL-C • Randomly allocate persons into approximately equal sized groups Polymorphisms included in the NPC1L1 Genetic LDL-C Score SNP

Position (SNP_hg19)

rs217386 rs2073547 rs7791240 rs10234070 rs2300414

chr7:44600695 chr7:44582331 chr7:44602589 chr7:44537696 chr7:44682938

Exposure allele frequency*

LDL Effect Size (mg/dl)

p-value

Sample Size

0.4077 0.8061 0.9090 0.9037 0.9301

1.1253 1.5035 1.3175 0.9145 1.0943

1.20E-19 1.92E-21 1.84E-10 1.52E-06 5.45E-06

173,021 169,889 161,845 160,051 115,286

Polymorphisms included in the HMGCR Genetic LDL-C Score SNP

Position (SNP_hg19)

rs12916 rs5744707 rs16872526

chr5:74656539 chr5:74890618 chr5:74675717

Exposure allele frequency*

LDL Effect Size (mg/dl)

p-value

Sample Size

0.5686 0.8971 0.8971

2.2723 1.7019 1.2617

7.79E-78 5.85E-19 2.36E-08

168,357 172,928 173,009

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

2x2 Factorial Mendelian Randomization HMGCR LDL-C score

naturally randomize

Below Median (reference)

Above Median (Lower LDL-C)

NPC1L1 LDL-C score

naturally randomize

Below Median (reference)

Above Median (Lower LDL-C)

Below Median (reference)

Above Median (Lower LDL-C)

Reference

Lower LDL-C via NPC1L1

Lower LDL-C via HMGCR

Lower LDL-C via NPC1L1 & HMGCR

Placebo

Ezetimibe

Statin

Ezetimibe/Statin

Lifetime Risk of CHD events

Baseline Characteristics â&#x20AC;˘ No difference in baseline characteristics: confirms random allocation

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

2x2 Factorial Mendelian Randomization

Group

LDL-C Effect Size (mg/dl)

Both NPC1L1 & HMGCR LDL-C Scores above median

-5.8

HMGCR LDL-C Score above median

-2.9

NPC1L1 LDL-C Score above median

-2.4

ORCHD (95%CI)

0.892 (0.839-0.948) p = 2.4x10-4

0.947 (0.914-0.982) p = 3.3x10-3

0.952 (0.923-0.983) p = 2.6x10-3

| 0.85

| 0.90

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

| 0.95

| 1.0

External Validation • Up to 62,240 cases of CHD and up to 127,299 control subjects • Comparison of effect of 10 mg/dl lower LDL-C mediated by combined effect of polymorphisms in either genetic LDL-C score

Genetic LDL-C Score

ORCHD (95%CI) Adjusted per 10 mg/dl LDL-C

HMGCR LDL-C Score

0.828 (0.775-0.885) p = 5.5x10-8

NPC1L1 LDL-C Score

0.823 (0.741-0.915) p = 3.1x10-4

| 0.70

| 0.80

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

| 0.90

| 1.0

http://www.CARDIOGRAMPLUSC4D. org

Rare Inactivating NPC1L1 Mutations • Carriers: 12 mg/dL lower LDLC and ORCHD = 0.47 (95%CI: 0.25-0.89) • 29,954 case of CHD (11 carriers) vs 83,140 (71 carriers)

Myocardial Infarction Genetics Consortium. N Engl J Med 2014;371(22):2072-82).

Consistent Effect Per Unit Lower LDL-C on Risk of CHD • •

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

http://www.CARDIOGRAMPLUSC4D. org

Log-Linear Effect of Lower LDL-C on CHD

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9.

Log-Linear Effect of Lower LDL-C on CHD

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9.

Log-Linear Effect of Lower LDL-C on CHD

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9.

Log-Linear Effect of Lower LDL-C on CHD

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Cannon CP, et al. AHA, November, 17 2014.

Log-Linear Effect of Lower LDL-C on CHD Cumulative Effect of Lifelong LDL-C

Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Cannon CP, et al. AHA, November, 17 2014.

IMPROVE-IT Results Primary Outcome (ITT)

Secondary Outcome: CV death, MI, stroke

â&#x20AC;˘ Results: Adding ezetimibe to statin resulted in linearly additive effect on LDL-C (15.8 mg/dl) and log-linearly additive effect on CHD

â&#x20AC;˘ Precisely as predicted by the naturally randomized genetic data

Cannon CP, et al. AHA, November, 17 2014.

Low dose statin plus ezetimibe v.s high dose statin Unadjusted

Adjusted per 5 mg/dL lower LDL-C

â&#x20AC;˘ Effect of lower LDL-C on CHD risk mediated by HMGCR alone is the same as effect of lower LDL-C mediated combined effect of HMGCR and NPC1L1 per unit lower LDL-C Ference, BA et al. J Am Coll Cardiol 2015;doi:10.1016/j.jacc.2015.02.020).

Conclusions from Naturally Randomized Data • Lower LDL-C mediated by polymorphisms in the NPC1L1 gene is casually associated with lower risk of CHD

• The effect of lower LDL-C on risk of CHD mediated by polymorphisms in NPC1L1 and HMGCR is approximately the same per unit lower LDL-C • Combined polymorphisms in NPC1L1 and HMGCR have independent linearly additive effects on LDL-C and a loglinearly additive effects on risk of CHD Naturally randomized genetic evidence agrees very closely with randomized IMPROVE-IT trial evidence

Implications for Treatment with Ezetimibe • No biological difference in effect of lower LDL-C on risk of CHD mediated by inhibition of NPC1L1 or HMGCR • Lowering LDL-C by inhibiting NPC1L1 with ezetimibe, inhibiting HMGCR with a statin or both should reduce risk of CHD proportional to absolute achieved reduction in LDL-C regardless of which treatment is used • Combination ezetimibe and low dose statin should be as effective as high dose statin at reducing CV events with potential for fewer dose-dependent statin side-effects

N Engl J Med. 2015 Jun 3. [Epub ahead of print]

Editorial • Overall, IMPROVE-IT provides us with important information on the value of lowering LDL cholesterol levels, regardless of the agent used. • These data help emphasize the primacy of LDL cholesterol lowering as a strategy to prevent coronary heart disease. • Perhaps the LDL hypothesis should now be considered the “LDL principle”. N Engl J Med. 2015 Jun 3. [Epub ahead of print]

Lipid lowering drugs in outcome trials

Drug

Monotherapy

Combination with statins

Statin

++++

not applicable

++ (Sharp; Improve-IT)

Bile acid binding resin

Niacin

- (AIM-high; HPS2-Thrive)

Fibrate

- (Accord)

+/-

- (Origin)

Ezetimibe

Omega 3 FA

Reclassification of LLT

PCSK9 monoclonal antibody Future star?

NEJM 2015;372:1500-1509

NEJM 2015;372:1489-1499

FDA approved Evolocumab & Alirocumab soon in 2015

Take Home Message (1)  LDL is still the primary goal of dyslipidemia therapy

 For high risk patients: intensive treatment is indicated (Ex: Crestor, Lipitor, Vytorin..)  For low risk patients: individualized therapy is suggested

under risk-benefit consideration  The concept of ‘The lower, the better’ is still correct after

IMPROVE-IT study  Non-statin lowering therapy of LDL with ezetimibe reduces cardiovascular events in IMPROVE-IT study

Take Home Message (2) •Statin together with ezetimibe is currently the most potent approach to reduce LDL-cholesterol in Taiwan

•Guidelines must be adjusted according to IMPROVE-IT study •PCSK9 inhibitor may be the future star for more aggressive LDL lowering therapy • However, we still need further evidence

感謝聆聽謝謝指教

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