LDL

, MD, FESC, FAHA

-
-



, ab,

AstraZeneca, Bayer, Sanofi, Pfizer,
Vianex, MSD, Unilever, Boehringer,
Novartis, Abbott, Galenica, Amgen,
Specifar, Menarini, Merck,
Pharmaswiss, Winmedica

Akira
Endo

HO
Compactin
O
H 3C

O
O

O
H

CH3

4S: Effect of LDL-C Lowering on Coronary Events in

Secondary Prevention Trial in Men and Women
10
5
0
-5
-10
%+ -15
-20
-25
-30
-35
-40
-45

Nonfatal
MI/CHD CHD All-cause
death death mortality
LDL-C
HDL-C
Subjects: 4,444
8

TC

(81% men, 19%

women)
Age range: 35-70 yr
Mean baseline TC: 261 mg/dL
Mean baseline LDL-C: 188
mg/dL

-25
-30
-34*

-35

*P<0.00001.

95% CI: -27 to -54.

P=0.003.

-42

Duration: 5 yr
Intervention: Simvastatin
20-40 mg/day

4S Group. Lancet. 1994;344:1383-1389.

HPS: Effects of Simvastatin on Cause-Specific Mortality

Statin
(10,269)
587

Placebo
(10,267)
707

Other vascular

194

230

All vascular

781 (7.6%)

937 (9.1%)

Neoplastic

359

345

Respiratory

90

114

Other medical

82

90

Nonmedical

16

21

Cause of death
CHD

All nonvascular

All causes

Statin better

0.83 (0.75-0.91)
17% reduction
(P<0.0001)

547 (5.3%)

570 (5.6%)

1,328 (12.9%)

1,507 (14.7%)
0.4

Placebo better

0.6

0.95 (0.85-1.07)
5% reduction
(P=0.4)
0.87 (0.81-0.94)
13% reduction
(P=0.0003)
0.8 1.0 1.2
RR with 95% CIs

HPS Collaborative Group. Lancet. 2002;360:7-22.

1.4

Pravastatin or Atorvastatin in Infection

Therapy (PROVE IT): Study Design
Patient population
Men and women aged
18 years

Hospitalized within 10
days of acute MI or highrisk unstable angina (UA)
TC 240 mg/dL

Atorvastatin 80 mg
(n=2099)
4162 patients

Stable condition, enrolled

after percutaneous
coronary intervention
(PCI), if planned

Pravastatin 40 mg
(n=2063)
18 to 36 months

Primary efficacy end point

Composite of death from any cause, MI, documented UA requiring

rehospitalization, revascularization, and stroke

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

PROVE IT: Early and Sustained Benefit With

Atorvastatin Compared With Pravastatin
Death or major cardiovascular event
(%)

Occurrence of primary composite end point

(death, MI, UA requiring rehospitalization, revascularization, stroke)
30
25

Pravastatin
(40 mg)

20

16% RRR in
composite
end point
P=.005

Atorvastatin
(80 mg)

15
10
5
0
0

12 15 18 21
Follow-up (months)

Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

24

27

30

PROVE-IT Substudy: Primary

End Point* and Achieved LDL-C Levels

Achieved LDL (mg/dL)

Hazard Ratio
>80100

Referent

>6080
1.07)

0.80 (0.59,

>4060
0.92)

0.67 (0.50,

40
0.91)

0.61 (0.40,

0
Lower Better
Better

2
Higher

*All-cause mortality, myocardial infarction, coronary revascularization, unstable

angina, and stroke.

Adjusted for multiple baseline characteristics, including LDL-C level.

Significantly lower than the referent group.

Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

PROVE-IT Substudy:
Major Safety Outcomes*

Achieved LDL-C (mg/dL)

>80-100
(n=256)

>60-80
(n=576)

>40-60
(n=631)

40
(n=193)

P (trend)

Myalgia

6.4

4.3

6.2

5.7

0.75

Myositis

0.4

0.6

0.6

0.64

ALT >3X ULN

3.2

3.0

3.2

2.6

0.98

Hemorrhagic stroke

0.4

0.2

0.12

Retinal adverse event

0.4

0.9

1.0

0.48

Death (all cause)

1.1

1.4

1.3

0.5

0.59

Adverse Event (%)

*Percent of subjects in each subgroup.

ALT=alanine aminotransferase;
ULN=upper limit of normal.
Adapted from Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

ASTEROID -
(n=507)
(CAD)

rosuvastatin 40 mg (n=507)
(PCI)
18
:
:

2
0

1
6

3
13

QCA
IVUS

4
26

5
39

Nissen S. Atheroscler Suppl 2003; 4: 27

6
52

7
65

8
78

9
91

10
104

QCA
IVUS

Baseline characteristics - lipids

ASTEROID
Baseline level;
total population
(n=346*)

Baseline level
mg/dL
mean (SD)

During treatment
level mg/dl
mean (SD)

TC
LDL-C

204 (41)
130 (34)

134 (25)
61 (20)

HDL-C
Non-HDL-C

43 (11)
161 (40)

49 (13)
85 (23)

TG
ApoB
ApoA-1

152 (82)
128 (29)
139 (27)

121 (57)
74.5 (22)
150 (31)

*3 out of 349 patients completing the trial were missing lab data
Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

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

50

60

70

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

110

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

120

JUPITER

Justification for the Use of

statins in Primary prevention: an
Intervention Trial Evaluating
Rosuvastatin

Ridker P et al. N Eng J Med 2008;359: 2195-2207

CRP is a strong independent predictor of CV

events in women
Lp(a)
Homocysteine
IL-6
TC
LDL-C
sICAM-1
SAA
ApoB
TC/HDL-C
CRP
CRP + TC/HDL-C
0

1.0

2.0

4.0

6.0

Relative risk of future CV events

Apo=apolipoprotein; CRP=C-reactive protein; CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin;
LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular
adhesion molecule 1; TC=total cholesterol

Blake GJ, Ridker PM. Circ Res 2001; 89: 763771

JUPITER study design

No history of CAD
men 50 yrs

Rosuvastatin 20 mg (n=8901)
Placebo

women 60 yrs
LDL-C <130 mg/dL

run-in
Placebo (n=8901)

CRP 2.0 mg/L

Visit:
Week:

1
6

2
4

Lead-in/
eligibility

3
0

4
13

6-monthly

Final

Randomisation

Lipids
CRP
Tolerability

Lipids
CRP
Tolerability

Lipids
CRP
Tolerability
HbA1C

Median follow-up 1.9 years

CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c=glycated haemoglobin

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER - Primary Endpoint

Placebo

0.06

Hazard Ratio 0.56

(95% CI 0.46-0.69)
P<0.00001

0.04

Rosuvastatin 20 mg

NNT for 2y = 95
5y* = 25

0.00

0.02

Cumulative Incidence

0.08

Time to first occurrence of a CV death, non-fatal stroke, non-fatal

MI, unstable angina or arterial revascularization

Follow-up (years)

Number at Risk
Rosuvastatin
Placebo

8,901
8,901

8,631
8,621

8,412
8,353

6,540
6,508

*Extrapolated figure based on Altman and Andersen method

3,893
3,872

1,958
1,963

1,353
1,333

983
955

544
534

157
174

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER - Total Mortality

0.06

Death from any cause

Placebo

0.02

0.03

0.04

Rosuvastatin 20mg

0.00

0.01

Cumulative Incidence

0.05

Hazard Ratio 0.80

(95% CI 0.67-0.97)
p=0.02

0
Number at Risk
Rosuvastatin 8,901
Placebo
8,901

Follow-up (years)
8,847
8,852

8,787
8,775

6,999
6,987

4,312
4,319

2,268
2,295

1,602
1,614

1,192
1,196

683
684

227
246

Ridker P et al. N Eng J Med 2008;359: 2195-2207

IMPROVE-IT: 1-3

(NSTEMI, STEMI
(STEMI 30% )

10

EZ/Simva
10/40 mg

Simva
40 mg

N = 18.1412

2,5
FDA 80 mg.
( ) LDL 97 mg/dL 10.000 .
IMPROVE IT = IMProved Reduction of Outcomes: Vytorin Efficacy International Trial.
1. Cannon CP et al. Am Heart J. 2008;156:826-832. 2. Califf RM, et al. Am Heart J. 2010;159:705-709.
3. http://clinicaltrials.gov/ct2/show/NCT00202878?term=improve-it&rank=1

LDL-c 1

95 mg/dL (2,5 mmol/L)

104 mg/dL (2,7 mmol/L)

80 mg/dL (2,1 mmol/L)

.
80 mg LDL-C >79 mg/dL,
2011.

LDL-C

1. Blazing MA et al. Am Heart J. 2014; doi: 10.1016/j.ahj.2014.05.004.

 LDL-C

1 Yr Mean

LDL-C

TC

TG

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

in mg/dL

-16.7

-19.3

-16.7

+0.6

-0.5

Median Time avg

69. vs. 53.7 mg/dL

http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf

 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

6,4 % RRR

http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf

7-year event rates

 -
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

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

No diabetes
Diabetes

0.7

Ezetimibe/Simva
Better

1.0

Simva
Better

1.3

7-year
event rates

*p-interaction = 0.023, otherwise > 0.05

http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf

 IMPROVE-IT vs. CTT :

CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.

http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf


IMPROVE-IT:
:
:
:
)
:

LDL-C


( LDL-C 53 vs. 70 mg/dL 1

LDL-C,


http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf

Henry C. Ginsberg, MD
College of Physicians & Surgeons , Columbia University, New York
For The ACCORD Study Group

Characteristic

Mean or % Characteristic

Mean or
%

Age (yrs)

62

Total Cholesterol
(mg/dl)

175

Women %

31

LDL-C (mg/dl)

101

HDL-C (mg/dl)

38

Race / Ethnicity
White %

68

Triglyceride (mg/dl)*

162

Black %

15

Blood pressure (mm

Hg)

134/74

Hispanic %
Secondary
prevent %
DM duration (yrs)*
A1c (%) *
BMI (kg/m )
2

7
37
9

Serum creatinine
(mg/dl)

0.9

Current smoking %

15

On a statin %

60

8.3

On another LLA %

32

On Insulin %

Median values

8
33

Primary Outcome By Treatment Group and Baseline Subgroups

Trial
(Drug)

HHS
(Gemfibrozil)

BIP
(Bezafibrate)

FIELD
(Fenofibrate)

ACCORD
(Fenofibrate)

Primary Endpoint:
Entire Cohort
(P-value)

-34% (0.02)

Lipid Subgroup
Criterion

TG > 200 mg/dl

LDL-C/HDL-C
> 5.0

Primary
Endpoint:
Subgroup

-71%

TG > 200 mg/dl

-7.3% (0.24)

-11%

-8%

(0.16)

(0.32)

-39.5%
TG > 204 mg/dl
HDL-C < 42
mg/dl

-27%

TG > 204 mg/dl

HDL-C < 34
mg/dl

-31%

Relationship between the Change in Percent Atheroma Volume and LDL Cholesterol in
Regression-Progression Trials Using Intravascular Ultrasonography

Nissen SE et al. N Engl J Med 2007;356:1304-1316

ILLUMINATE
15000
torcetrapib 60mg
10-80 mg 5 .

82 51 torcetrapib,
,
.


PCSK9
LDL-C
PCSK9

LDL-C

CHD

R46L

ARIC, DHS

15%1

47%1

Y142X C679X

ARIC, DHS

28-40%1,2

88%1

CGPS

11%3

46%3

R46L

1% 3% 1

LDL-C 1

1
1.

2.

LDL-R / PCSK9
Cohen JC,
Boerwinkle
E, Mosley TH, Hobbs
HH., N Engl J
Med. 2006;
354:1264-1272. LDL-C

Cohen J, Pertsemlidis4 A, Kotowski IK, et al., Nat Genet. 2005, 37:161-165.

3. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjrg-Hansen A. J. Am. Coll. Cardiol.

2010;55:2833-2842.
4. Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106:9546-9547.

PCSK9 as a therapeutic target of

dyslipidemia
Nabil G Seidah

Expert Opin. Ther. Targets (2009) 13(1)

 LDL-R PCSK9


LDL

PCSK9

LDL

LDL

LDL, LDL-R
PCSK9

PCSK9

LDL-R

SREBP*

LDL-R

PCSK9

*[SREBP] =
1. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
2. Dubuc G, Chamberland A, Wassef H, et al. Arterioscler Thromb Vasc Biol. 2004;24:1454-1459.

LAPLACE-2: LDL-C Response at Mean of

Weeks 10 and 12
Mean percent change from
baseline in LDL-C and 95% CI

Evolocumab Q2W & QM: 63 to 75% reductions in LDL-C versus placebo

Ezetimibe: 19 to 32% reductions in LDL-C versus placebo

Atorvastatin
80 mg

Placebo Q2W
Placebo QM

Rosuvastatin
40 mg

Atorvastatin
10 mg

Ezetimibe QD + Placebo Q2W

Ezetimibe QD + Placebo QM

Rosuvastatin
5 mg

Simvastatin
40 mg

Evolocumab Q2W
Evolocumab QM

All treatment differences versus placebo and ezetimibe were statistically significant (p<0.001). Vertical lines represent 95% CIs.
No notable differences were observed between the mean of Weeks 10 and 12 and Week 12 alone.
LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly

Robinson JG, et.al. JAMA 2014;311:187082

48

 FOURIER

Finding Cardiovascular OUtcomes in Response to PCSK9 Inhibition in Subjects with

Elevated Risk

A Double-blind, Randomized, Placebo-controlled, Multicenter Study

Assessing the Impact of Additional LDL-Cholesterol Reduction on
Major Cardiovascular Events when AMG 145 is Used in
Combination with Statin Therapy in Patients with Clinically Evident
Cardiovascular Disease
N = 22500

Information from clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT01764633