Lipid is evolving

DyslipidemiaVascular disease

Statin Beyond

관동의대제일병원

내과박정배

&A

Dyslipidemia 와혈관질환,

그연결고리는?

약80%가

체내에서생성

약20%가

음식물에서흡수

Quantity of cholesterol

in the body

Bile

acid

s

배설

동맥경화증의위험요인

Coronary Heart Disease

Other

High blood

cholesterol

Smoking

Aging

Obesity

Hypertension

Diabetes

mellitus

Heredity

흡연이고혈압의위험요인인것처럼, 혈액중에콜레스테롤의양이많으면심장질환과동맥경화의위험요인이된다.

Compliant

Systole Diastole

Arterio and Atherosclerosis

Systole Diastole

Constant Stroke Volume

Aorta

Pulse pressure

compliant stiffened

죽상경화증(atherosclerosis) 과동맥경화증(arteriosclerosis)

O’Leary DH et al. N Engl J Med.1999;340(1):14-22

Vascular event (MI or Stroke) rate and IMT

Birgelen C et al. Circulation 2004;110:1579

Vascular event and Plaque

Pulse wave change (eg,augmentation index)

Evolving of Dyslipid Vascular disease

Vascular imagingEndothelial function test

Markers of Atherosclerosis and arteriosclerosis

are risk factors for adverse CV outcomes

Risk of CHD by Multiple Risks & Cholesterol

Kannel J. Am Coll Cardiol. 1990

8-y

ea

r p

rob

ab

ilit

y

(pe

r 1

00

0)

Cholesterol mg/dL 185↔335 185↔335 185↔335 185↔335

(mmol/L) (4.8↔8.7) (4.8↔8.7) (4.8↔8.7) (4.8↔8.7)

Glucose Intolerance 0 + + +

Systolic BP (mmHg) 105 195 195 195

Cigarettes 0 0 + +

LVH on ECG 0 0 0 +

60

50

40

30

20

10

0

60.2

34.6

23.2

3.9

&Q

ADyslipidemia, 혈관질환과의연결고리를어떻게끊을것인가?

Dyslipidemia Vascular disease

Statin & beyond

Meta-analysis of 38 1o & 2o prevention trials, with 98,000 patients

Mortality in CHD, p=0.012

Total mortality, p=0.04

Benefit of Lowering Cholesterol

Gould AL et al. Circulation 1998;97:946–952

Cholesterol reduction (%)

Mortalitylog oddsratio

0 4 8 12 16 20 24 28 32–1.0

–0.8

–0.6

–0.4

–0.2

0.0

적정한감량수치는기존체중의 5~7% 감량

음식: 포화지방 7% ↓ · 트랜스불포화지방산 1% ↓

·콜레스테롤 200mg/d ↓ /전체칼로리

염분섭취량 : 1200~2300mg/일

운동: 심혈관계질환예방 - 중등도 150분/강력한운동 90분 /주체중감량및유지: 중등도/강력한운동 7시간/주

금연: 금연권고+ 담배를끊고자하는의지평가필요.

생활습관개선요법이최대 3개월까지

2007 AHA·ADA

"당뇨병환자심혈관질환예방" 생활습관

지혈이상증의치료

고지혈증치료의기본원칙1) 고지혈증의종류에따라식이요법과운동처방을약 3개월동안시행한다.

2) 식이요법과운동요법이효과가없을때약물치료를시작한다.

3) 약물치료를시작한뒤에도식이요법과운동요법을병행한다.

운동식이요법

약물투여

Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD

Highest-risk patients, including those with 1) known CVD or 2)

diabetes plus one or more additional major CVD risk factor

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

LDLcholesterol

(mg/dl)

<70

<100

Goals

Non-HDL cholesterol

(mg/dl)

<100

<130

ApoB

(mg/dl)

<80

<90

ADA. Diabetes Care 2008;31:811-822

ADA and NCEP ATP IIIRecommendations for Lipid Goals in Patients

first-line therapy

for reducing LDL levels

in patients at high risk for

atherosclerotic cardiovascular disease (ASCVD).

Statins:

* 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

LD

L-C

(S

E)

Re

du

cti

on

(%

)

Rosuvastatin(mg)

10

-45.8*

Pravastatin(mg)

10 20 40

-29.7

-24.4

-20.1

–60

–50

–40

–30

–20

–10

0

–52.4†

–55.0‡

20 40

Atorvastatin(mg)

10 20 40

-36.8

-47.8

-42.6

–51.1

80

Simvastatin(mg)

10 20 40

-28.3

-35.0

-38.8

–45.8

80

Percentage Change in LDL-C: Pairwise Comparisons with Rosuvastatin

Primary

prevention trials

Secondary

prevention trials

50 70 110 130 150 170 19090 210

% P

ati

en

ts w

ith

CH

D E

ven

t

LDL cholesterol

CARE-Rx

4S-Rx

LIPID-PL

4S-PL

CARE-PL

LIPID-Rx

AFCAPS-Rx

WOSCOPS-Rx

WOSCOPS-PL

AFCAPS-PL

25

20

15

10

5

0

ASCOT-PL

ASCOT-Rx

HPS-Rx

HPS-PL

HPS

LRC-PLLRC-Rx

POSCH-PL

POSCH-Rx

non statin trials

Statin trials

(mg/dL)

1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)

TNT-80A

TNT-10A

Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy

얼마나낮출것인가?

Stephen J Nicholls et al., JAMA 2007:297:499-508

Modified from Kannel WB et al., Am Heart J 1985:110:1100-1107

Modified from Paul Muntner et al., Presented at ACC in 2007

0.01

0.02

0.03

0.04

0.05

≧190160-189

130-159100-129

＜100≧60 50-59 40-49 ＜40

HDL-C(mg/dL)

（mm/5year） ARIC Study

Inc

rea

se

of

IMT

0

0.5

1.5

2

3

220

160

10085 55 25

HDL-C(mg/dL)

2.5

1

Framingham Study

Re

lati

ve

ris

k f

or

CV

D

Not only LDL-C but also HDL-C are the key factor for the regression of

atherosclerosis and prevention of CVD

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

Risk

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

1% decrease

in LDL-C reduces

CHD risk by

1%

1% increase

in HDL-C reduces

CHD risk by

3%

* 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

Rosuvastatin(mg)

Atorvastatin(mg)

Simvastatin(mg)

Pravastatin(mg)

10 20 40

3.2

4.4

5.6

10 20 40 80 10 20 40 0

2

4

6

8

10

12

5.7

4.84.4

2.1

7.7*

9.5†9.6‡

10 20 40 80

5.3

6.0

5.2

6.8

ITT = intention-to-treat

Jones PH, et al. Am J Cardiol. 2003;92:152-160

Percentage Change from Baseline in HDL-C at Week 6 by DoseH

DL

-C I

ncr

ease

(%

)

To Study the Disease you Need to Image the Vessel Wall

Carotid Intima Medial Thickness

Placebo; change in CIMT (95% CI) Rosuvastatin 40 mg; change in CIMT (95% CI)

Crouse JR III et al. JAMA 2007;297 (12):1344–1353

Time (years)

Ch

an

ge i

n I

MT

of

12

caro

tid

sit

es (

mm

)

-0.01

+0.01

0.00

+0.02

21

+0.03

P=NS(rosuvastatin vs. zero slope)

placebo+0.0131 mm/yr (n=252)

rosuvastatin 40 mg-0.0014 mm/yr (n=624)

Pro

gressio

n

Reg

ressio

n

P<0.0001 (rosuvastatin vs. placebo)

METEOR studyA Rate of changes of max. IMT at 12 carotid sites

Rosuvastatin vs placebo

LumenArea

EEM Area

Atheroma Area

Ultrasound Determination of Atheroma Area

Precise Planimetry of EEM and Lumen Borders

with Calculation of Atheroma Cross-sectional Area

Atheroma Burden and Incident Clinical Events

Nicholls S. AHA Scientific Sessions 2007

Ch

an

ge P

AV

Yes No

P=0.04

Change Percent Atheroma Volume

PA

V

Baseline Percent Atheroma Volume

Yes No

P<0.001

Incidence of cardiovascular death, myocardial infarction, hospitalisation for unstable angina, stroke and coronary revascularisation

ILLUSTRATE (N=1180)

42.0

38.5

35.0

0.6

0.3

0.0

REVERSAL: Benefit of Intensive LDL-C Lowering on Plaque Progression

Percen

t ch

an

ge in

ath

ero

ma v

olu

me

Progression (P=0.001)

No change (P=0.98)

P=0.02 between treatment groups

pravastatin 40 mg

atorvastatin 80 mg

Nissen SE et al. JAMA 2004;291:1071–1080

3

2

1

0

-1

REVERSALComparison of % LDL Cholesterol Reduction and

Change in Atheroma Volume

% Change in LDL Cholesterol

Ch

an

ge i

n A

thero

ma V

olu

me,

mm

3

50% LDL-C reduction

-15

-10

-5

0

5

10

15

20

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20

ASTEROID: Regression with High Dose Statin Therapy

%

349 patients treated with rosuvastatin 40 mg for 2 yearsLDL-C 60.8 mg/dL and increase HDL-C by 14.7%

Percent Atheroma Volume

Atheroma Volume Most Diseased 10 mm

Total Atheroma Volume

P<0.001P<0.001

mm

3

mm

3

-0.79 -5.6-12.5

0.0

-0.5

-1.0

P<0.001

0.0

-2.5

-7.5

-5.0

0

-5

-15

-10

Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565

A

ASTEROID rosuvastatin

50 60 80 90 100 110

0.6

1.2

1.8

Relationship Between LDL-C Levels and Change in Percent Atheroma Volume for

Several IVUS Trials

Med

ian

ch

an

ge i

n p

ercen

t ath

erom

a v

olu

me (

%)

Mean LDL-C (mg/dL)

0

-1.2

-0.6

70 120

A-Plus placebo

CAMELOT placebo

REVERSAL pravastatin

REVERSAL atorvastatin

R2 = 0.97 P<0.001

Progression

Regression

Nissen S et al. JAMA 2006

Cholesterol Treatment Trialists’ (CTT):

Relative Risk of Major Vascular Events

-20%

-10%

0%

10%

20%

30%

40%

50%

60%

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

LDL cholesterol difference (mmol/L)

Relative

risk

reduction

22% reduction per 1 mmol/L

lower LDL-C14 statin trials

Baigent C. Lancet 2005 Oct 8; 366:1267-78

&A

Statin and beyond?

•Rosuvastatin 20 mg (N=8901) •MI•Stroke

•Unstable• Angina

•CVD Death•CABG/PTCA

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

•4-week run-in

Ridker et al, Circulation 2003;108:2292-2297.

•No Prior CVD or DM•Men >50, Women >60

• LDL <130 mg/dL• hsCRP >2 mg/L

•Placebo (N=8901)

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

Lowering CRP with Statin Therapy

Reduces CV Risk: PROVE-IT

n

Number

recurrent

events

Number of

events/

100 pt yr

Study group(levels after statin)

Low LDL-C/low CRP

Low LDL-C/high CRP

High LDL-C/low CRP

High LDL-C/high CRP

1018

899

742

1086

48

56

47

92

2.4

3.2

3.1

4.6

Ridker PM et al. N Engl J Med 2005;352:20-28.

hs-CRP?

JUPITER Primary Trial Endpoint: MI, Stroke, UA/Revascularization, CV Death

Ridker et al. NEJM 2008;359(21):2280-2

Cu

mu

lati

ve In

cid

ence

Number Needed to Treat (NNT5) = 25

HR 0.56, 95% CI 0.46-0.69

P < 0.00001

JUPITER Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;

Percentage change between rosuvastatin and placebo

-60

-50

-40

-30

-20

-10

0

10 LDL-C HDL-C TG hsCRPP

ercen

tag

e c

han

ge

from

baselin

e (

%)

50%

4%

17%

37%

p<0.001

p<0.001*

p<0.001

p<0.001

*P-value at study completion (48 months) = 0.34Ridker P et al. N Eng J Med 2008;359: 2195-2207

0 1 2 3 4

0.0

00

0.0

05

0.0

10

0.0

15

0.0

20

0.0

25

Cu

mu

lati

ve I

ncid

en

ce

Number at RiskFollow-up (years)

Rosuvastatin

Placebo

8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161

8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

HR 0.57, 95%CI 0.37-0.86

P= 0.007

Placebo 60 / 8901

Rosuvastatin 34 / 8901

- 43 %

JUPITERTotal Venous Thromboembolism

Artery or vein?

Rosuvastatin in Older Patients with Systolic Heart Failure (CORONA)

NEJM 2007. 357:2248-2261

일차종말점(심혈관계사망, 비치명적심근경색, 비치명적뇌졸중의첫발생까지의시간)

Hazard ratio

= 0.84 (0.7-1.0)

Heart failure?

Williams, B. et al. Circulation 2009;119:53-61

CAFE-LLA: Statin therapy does not influence

central aortic pressure or hemodynamics

Arteriosclerosis?

CAFÉ -BLA: Lower central aortic BP with

newer vs older antihypertensive regimen

despite similar brachial BP

140

135

130

125

120

115

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

Time (years)

mm Hg

Brachial SBP

Central aortic SBP

CAFE Investigators. Circulation. 2006;113:1213-25.

Amlodipine

± perindopril

Atenolol

± thiazide

A

&A

Statin 안전한가?

http://www.circ.ahajournals.org/cgi/content/full/111/23/3016

The Issue of Statin Safety

Where do We Stand?

Scott M. Grundy, MD, PhD

Circulation. 2005;111:3016-3019.

higher risk for severe myopathy

advanced age (especially >80 years) (women > men)

small body frame and frailty

multisystem disease (eg, CRF, especially if caused by diabetes)

perioperative periods

multiple medications (especially gemfibrozil, cyclosporine, azole

antifungals, itraconazole and ketoconazole, macrolide antibiotics,

erythromycin and clarithromycin, HIV protease inhibitors, the

antidepressant nefazodone, and verapamil)

consumption of large quantities of grapefruit juice (>1 quart/day)

alcohol abuse (which independently predisposes to myopathy)

Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C; American College of

Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI Clinical

Advisory on the Use and Safety of Statins. Circulation. 2002; 106: 1024–1028

Deaths Due to Suicide, Cancer, and Hemorrhagic Stroke

Number (%) of patients

Quintile 1

<64 mg/dL

(114/1722)*

Quintile 2

64–<77 mg/dL

(529/1403)*

Quintile 3

77–<90 mg/dL

(1019/968)*

Quintile 4

90–<106 mg/dL

(1515/515)*

Quintile 5

106 mg/dL

(1718/266)*

Suicide 1 (0.1) 0 (0.0) 1 (0.1) 1 (0.0) 1 (0.1)

Cancer 21 (1.1) 37 (1.9) 34 (1.7) 32 (1.6) 30 (1.5)

Hemorrhagic stroke† 6 (0.3) 5 (0.3) 6 (0.3) 8 (0.4) 7 (0.4)

*Number of patients: atorvastatin 10 mg/atorvastatin 80 mg†Fatal and non-fatal

Number needed to treat for 1 year to:

Cause a GI Bleed1 Cause a Fatal GI Bleed1

Aspirin

Cause Severe Myositis2 Cause Fatal Myositis2

Statins

1Derry S, Loke YK. 20002Thompson PD, et al. 2003

Statin Safety in Perspective

248 2066

100,000 1,000,000

Evolving of Dyslipid Vascular disease

Target: LDL, … HDL-chol

Statins: dyslipidemia and vascular disease

and so athersclerotic CV disease

Statins and beyond:

useful in high inflammatory condition, VTE

not useful in systolic HF and arteriosclerosis

Statins and safety: quite safe

The Future of Best Practice

“Normal” plasma cholesterol

-

-

-

-

-

-700(18.0)

300(7.7)

200(5.2)

150(3.9)

100(2.6)

50(1.3)

0

Rat

Guinea pig

Sheep

Rabbit

Pig

Newborns

Normal adults

FH homozygotes

FH heterozygotes

Physiologic level forplasma LDL-chol

as predicted from receptorStudies 25 mg/dL

Cow

Camel