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New Concepts in the Evaluation

and
Treatment of Dyslipidemia
Nathan D. Wong, PhD, FACC
Professor and Director
Heart Disease Prevention Program
Division of Cardiology
University of California, Irvine
Past President, American Society
for Preventive Cardiology

1.20
1.100
1.063
1.019
1.006
0.95
5 10 20 40 60 80
1000
Chylomicron
Remnants
VLDL
LDL-R
HDL
2

HDL3DL
3

Particle Size (nm)
D
e
n
s
i
t
y

(
g
/
m
l
)

Chylomicron
VLDL
Remnants
Lipoprotein Particles
Lp(a)
IDL
Only these lipoprotein particles
found in plaque at biopsy.
1.050
Rationale for therapeutic lowering of Apo B lipoproteins: decrease the
probability of inflammatory response to retention
Tabas I et al. Circulation. 2007;116:1832-1844.
Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551-561.
Hoshiga M et al. Circ Res. 1995;77:1129-1135.
Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536-1540.
Merrilees MJ et al. J Vasc Res. 1993;30:293-302.
Nakata A et al. Circulation.1996;94:2778-2786.
Steinberg D et al. N Engl J Med. 1989;320:915-924.
High Plasma Apo B Lipoprotein
Levels Promote Atherogenesis
Blood
Apo B lipoprotein
particles
Modification
Macrophage
Monocytes bind to
adhesion molecules
Smooth muscle
Foam cell
Inflammatory
response
Lipid Atherogenesis
HDL
Liver
Advanced
fibrocalcific
lesion
Oxidative
modification
of LDL
LDL
+
VLDL
Cholesterol
excreted
Endothelial
injury
Adherence
of platelets
Release
of PDGF
High plasma
LDL
LDL infiltration
into intima
+
Macrophages
Foam cells
Fatty streak
LCAT
APO-A1
Other
growth
factors
lipid core
adventitia
adventitia
lipid core
Anti-atherosclerotic therapy
From Davies et al (1998)
Unstable
lesion
Stable
lesion
Proportion of U.S. Adults at Recommended
Lipid Levels in NHANES 2003-2004
0
10
20
30
40
50
60
70
80
Percent of
Adults
LDL-C HDL-C TG All
Men
Women
CVD
DM
Ghandehari and Wong et al, Am Heart J 2008
Genetic Causes of Dyslipidemia
Type I – Familial Hyperchylomicronemia
÷ Fasting triglycerides > 1000 mg/dl
÷ Defect in lipoprotein lipase or apo CII
÷ Not necessarily at increased risk of CAD
Type II - Familial Hypercholesterolemia (type II)
÷ LDL-C > 95
th
percentile for age and gender
÷ CAD in men by 3
rd
or 4
th
decade
÷ Defect in LDL receptor
÷ Autosomal dominant inheritance
÷ Prevalence 1:500
Familial Defective apo B 100
÷ Defective apo B alters LDLr handling
÷ Previously undetecable from FH


Genetic Causes of Dyslipidemia
Type III – Hyperlipoproteinemia
÷ Increased TC, VLDL, decreased HDL; Increased VLDL:TG
÷ Defect in apo E results in increased concentration of remnant particles
÷ Rare
Type IV – Familial Hypertriglyceridemia
÷ Increased TC (due to VLDL), TG, decreased LDL, HDL
÷ Results from hepatic overproduction of VLDL
÷ Prevalence 1:100 – 1:50; Association with CAD not as strong as FH
÷ Heterogeneous inheritance
÷ Very sensitive to diet and EtOH
Type V
÷ Increase in chylomicrons and VLDL
÷ Rare

Genetic Causes of Dyslipidemia
Familial Combined Hyperlipidemia
÷ Increased TC, LDL and/or triglycerides; decreased HDL
÷ Most common genetic dyslipidemia: prevalence 1:50
÷ Heterogenous inheritance
÷ Accounts for 10-20% of patients with premature CAD

Defects in HDL Metabolism
÷ Most often low HDL is secondary to other dyslipidemia
÷ Not all associated with increased CAD risk (e.g. apo AI
Milano
)
÷ Tangier’s Disease
÷ CETP defects result in increased HDL

Total Cholesterol Distribution:
CHD vs Non-CHD Population
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.
©1996 Reprinted with permission from Elsevier Science.
35% of CHD
Occurs in
People with
TC<200 mg/dL
150
200
Total Cholesterol (mg/dL)
250 300
No CHD
CHD
Framingham Heart Study—26-Year Follow-up
Low HDL-C Levels Increase CHD Risk Even
When Total-C Is Normal
Risk of CHD by HDL-C and Total-C levels; aged 48–83 y
Castelli WP et al. JAMA 1986;256:2835–2838
0
2
4
6
8
10
12
14
< 40 40–49 50–59 > 60
< 200
230–259
200–229
> 260
HDL-C (mg/dL)
1
4
-
y

i
n
c
i
d
e
n
c
e


r
a
t
e
s

(
%
)

f
o
r

C
H
D

Sarwar N, et al. Circulation. 2007;115:450-458.
a
Individuals in top versus bottom third of usual log-triglyceride values, adjusted for
at least age, sex, smoking status, lipid concentrations, and blood pressure (most)
CHD Risk Ratio* (95% CI)
1.72 (1.56–1.90)
2
1
Duration of follow-up
≥10 years 5902
<10 years 4256
Sex
Male 7728
Female 1994
Fasting status
Fasting 7484
Nonfasting 2674
Adjusted for HDL
Yes 4469
No 5689
N=262,525
Groups CHD Cases
Overall CHD Risk Ratio
a
Decreased Risk Increased Risk
CHD=coronary heart disease
HDL=high-density lipoprotein
Triglyceride Level Is Significant CHD Risk Factor:
Recent Meta-Analysis of 29 Studies (n=262,525)
(Sarwar et al., Circulation 2007)
 Triglyceride-rich lipoproteins carry cholesterol and promote
atherosclerosis*
 Very–low-density lipoprotein (VLDL) is precursor to low-density
lipoprotein (LDL)
 Hypertriglyceridemia (HTG) drives
÷ Cholesterol esters enrichment of VLDL (more atherogenic)
÷ ↓ LDL size (small, dense LDL are more atherogenic)*
÷ ↓ LDL-C (small, dense LDL carry less cholesterol)*
÷ ↓ High-density lipoprotein (HDL) size (small, dense HDL are unstable)
 HTG is linked to other proatherogenic states*
÷ Insulin resistance
÷ Proinflammatory state
÷ Prothrombotic state
÷ Prooxidative state
÷ Endothelial dysfunction
*Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease
How Can Hypertriglyceridemia
be Atherogenic?
Apolipoprotein
B
LDL=
130 mg/dL
Fewer Particles
More Particles
Cholesterol
ester
More
apolipoprotein B
Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.
Correlates with:
TC 198 mg/dL
LDL-C 130 mg/dL
TG 90 mg/dL
HDL-C 50 mg/dL
Non–HDL-C 148 mg/dL
Correlates with:
TC 210 mg/dL
LDL-C 130 mg/dL
TG 250 mg/dL
HDL-C 30 mg/dL
Non–HDL-C 180 mg/dL
TC=total cholesterol, LDL-C=low-density lipoprotein cholesterol,
TG=triglycerides, HDL-C=high-density lipoprotein cholesterol
Elevated Triglycerides Are Associated With
Increased Small, Dense LDL Particles
 Cholesterol per particle, BUT
 Subendothelial penetration
 Subendothelial binding
 Oxidized/modified
 LDL-receptor clearance
LDL=low-density lipoprotein
Why Is Small, Dense LDL More
Atherogenic?
 Significance of Non-HDL-C
 LDL-C levels incompletely measure the total
atherogenic burden
 When serum TG are >200 mg/dL, increased remnant
atherogenic lipoproteins heighten risk beyond predicted
by LDL-C
– Associated with substantially elevated VLDL-C
 VLDL-C and IDL-C are not accounted for by the
calculation of LDL-C
 Non-HDL-C = cholesterol concentration of all
atherogenic lipoproteins



Miller M, et al. Am J Cardiol 2009;101:1003-1008
Non-HDL-Cholesterol and CVD Risk
Very–low-density lipoprotein (VLDL)
 Made in the liver
 Triglycerides (TG) >> cholesterol esters (CE)
 Carries lipids from the liver to peripheral tissues
HDL
LDL
IDL
VLDL
A
t
h
e
r
o
g
e
n
i
c

L
i
p
o
p
r
o
t
e
i
n
s

N
o
n
-
H
D
L
;

A
p
o

B
-
1
0
0

c
o
n
t
a
i
n
i
n
g

Intermediate-density lipoprotein (IDL)
• Formed from VLDL due to lipase removal of TG
• Also known as a VLDL remnant
Low-density lipoprotein (LDL)
• Formed from IDL due to lipase removal of TG
• CE >> TG
High-density lipoprotein (HDL)
• Removes cholesterol from peripheral tissues
Lp(a)
Lipoprotein (a)
• Formed from LDL w/addition of apolipoprotein A
• Atherogenic and prothrombotic
Non-HDL Includes All Atherogenic
Lipoprotein Classes
Lp(a) in Atherogenesis: Another Culprit?
 Identical to LDL particle except for addition of apo(a)
 Plasma concentration predictive of atherosclerotic
disease in many epidemiologic studies, although
not all
 Accumulates in atherosclerotic plaque
 Binds apo B-containing lipoproteins and proteoglycans
 Taken up by foam cell precursors
 May interfere with thrombolysis
Maher VMG et al. JAMA. 1995;274:1771-1774.
Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176.
Lp(a): An Independent CHD Risk Factor in Men of the
Framingham Offspring Cohort
RR=relative risk; HT=hypertension; GI=glucose intolerance.
Bostom AG et al. JAMA. 1996;276:544-548.
1.9
1.8 1.8
1.2
2.7
3.6
RR
0.1
1
10
2
5
0.2
0.5 Lp(a) TC HDL-C HT GI Smoking
Placebo - Statin outcome trials
High-risk CHD patients
(high cholesterol)
Majority of
CHD patients
(broad range of
cholesterol levels)
Patients at high risk
of CHD (high
cholesterol)
Patients at low
risk of CHD
(low HDL-C)

Primary
prevention
Secondary
prevention
WOSCOPS
(pravastatin)
AFCAPS/TexCAPS
(lovastatin)
4S
(simvastatin)

HPS
(simvastatin)
CARE
(pravastatin)
LIPID
(pravastatin)
Continuum
of risk
22.6
12.9
8.44
7.9
2.8
P
l
a
c
e
b
o

M
I

r
a
t
e

p
e
r

1
0
0

s
u
b
j
e
c
t
s

p
e
r

5

y
e
a
r
s

PROSPER
(pravastatin)
Heart failure
CORONA
GISSI-HF
(rosuvastatin)
End stage 53.7
JUPITER
(rosuvastatin)
LDL-C achieved mg/dL (mmol/L)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - Placebo
AFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - Placebo
CARE - Placebo
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)
6
Secondary Prevention
Primary Prevention
Rx - Statin therapy
PRA – pravastatin
ATV - atorvastatin
200
(5.2)
PROVE-IT - PRA
PROVE-IT – ATV
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:e-version
TNT – ATV10
TNT – ATV80
LDL cholesterol and benefit in clinical trials
Is lower better ?
JUPITER
TNT
Cholesterol Treatment Trialists’ (CCT) Collaboration:
Efficacy and safety of cholesterol-lowering treatment:
prospective meta-analysis fo data from 90,056
participants in 14 randomized trials of statins
(The Lancet 9/27/05)

 Over average 5 year treatment period (per mmol/L
reduction—approx 40 mg/dl in LDL-C):
÷ 12% reduction in all-cause mortality
÷ 19% reduction in coronary mortality
÷ 23% reduction in MI or CHD death
÷ 17% reduction in stroke
÷ 21% reduction in major vascular events
÷ No difference in cancer incidence (RR=1.00).
 Statin therapy can safely reduce 5-year incidence of major
coronary events, revascularization, and stroke by about
20% per mmol/L (about 38 mg/dl) reduction in LDL-C
HPS: First Major Coronary Event
0.4 0.6 0.8 1.0 1.2 1.4
Nonfatal MI
Coronary death
Subtotal: MCE
Coronary
Noncoronary
Subtotal: any RV
Any MVE
Coronary events
Revascularizations
Type of Major
Vascular Event
Statin-
Allocated
(n = 10269)
Placebo-
Allocated
(n = 10267)
357 (3.5%) 574 (5.6%)
587 (5.7%) 707 (6.9%)
898 (8.7%) 1212 (11.8%)
513 (5.0%) 725 (7.1%)
450 (4.4%) 532 (5.2%)
939 (9.1%) 1205 (11.7%)
2033 (19.8%) 2585 (25.2%)
0.73 (0.67÷0.79)
P < 0.0001
0.76 (0.70÷0.83)
P < 0.0001
0.76 (0.72÷0.81)
P < 0.0001
Statin Better Placebo Better
Heart Protection Study Collaborative Group. Lancet. 2002;360:7÷22.
HPS—Simvastatin:
Vascular Events by Baseline LDL-C
Baseline
LDL-C (mg/dL)
Statin
(n = 10,269)
Placebo
(n = 10,267)
<100 282 (16.4%) 358 (21.0%)
100–129 668 (18.9%) 871 (24.7%)
>130 1083 (21.6%) 1356 (26.9%)
All patients 2033 (19.8%) 2585 (25.2%)
Event Rate Ratio (95% CI)
Statin Better Statin Worse
0.4 0.6 0.8 1.0 1.2 1.4
www.hpsinfo.org
0.76 (0.72–0.81)
P < 0.0001
Pravastatin or Atorvastatin Evaluation and Infection
Therapy (PROVE-IT)—TIMI 22 Study
3 6 9 12 15 18 21 24 27 30
Follow-up (months)
30
25
20
15
10
5
0
P =0.005
R
e
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t

M
I

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C
a
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i
a
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D
e
a
t
h

16% RRR
Atorvastatin
Pravastatin
ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk
reduction
Cannon CP et al. NEJM 2004;350:1495-1504
HMG-CoA Reductase Inhibitor:
Secondary Prevention
4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40
mg) for 24 months
0
5
10
15
20
25
30
60 80 100 120 140 160 180 200
TNT: Rationale
(1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)
Atorvastatin 80 mg
Atorvastatin 10 mg
Screening
TNT
?
Adapted from LaRosa et al. N Engl J Med. 2005:352:1425-1435.
LDL-C, mg/dL (mmol/L)
P
a
t
i
e
n
t
s

W
i
t
h

C
H
D

E
v
e
n
t
s

(
%
)

0
20
40
60
80
100
120
140
160
Atorvastatin 10 mg (n=5006)
Atorvastatin 80 mg (n=4995)
TNT: Changes in LDL-C by
Treatment Group
Final Screen 0 3 12 24 36 48 60
P<.001
Baseline
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
M
e
a
n

L
D
L
-
C

(
m
m
o
l
/
L
)

Mean LDL-C level = 101 mg/dL (2.6 mmol/L)
Mean LDL-C level = 77 mg/dL (2.0 mmol/L)
LaRosa et al. N Engl J Med. 2005;352:1425-1435.
M
e
a
n

L
D
L
-
C

(
m
g
/
d
L
)

Study Visit (Months)
TNT: Primary Efficacy Outcome Measure: Major
Cardiovascular Events*
* CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest,
fatal or nonfatal stroke.
LaRosa et al. N Engl J Med. 2005;352:1425-1430.
HR=0.78 (95% CI 0.69, 0.89); P<.001
P
r
o
p
o
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o
f

P
a
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s

E
x
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E
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t

0
0.05
0.10
0.15
Atorvastatin 10 mg
Atorvastatin 80 mg
Relative
risk
reduction
22%
0 1 2 3 4 5 6
Time (Years)
Mean LDL-C level = 77 mg/dL
Mean LDL-C level = 101 mg/dL
Meta analysis of moderate vs aggressive statin
therapy
Cannon et al (2006) JACC 48:438
Coronary death or MI
ACS
Stable CHD
Recent Coronary IVUS
Progression Trials
-1.2
-0.6
0
0.6
1.2
1.8
50 60 70 80 90 100 110 120
M
e
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a
n

c
h
a
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g
e

i
n

p
e
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e
n
t

a
t
h
e
r
o
m
a

v
o
l
u
m
e

(
%
)

Mean LDL-C (mg/dL)
REVERSAL
pravastatin
REVERSAL
atorvastatin
CAMELOT
placebo
A-Plus
placebo
ACTIVATE
placebo
Relationship between LDL-C and Progression Rate
ASTEROID
rosuvastatin
Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565
Rosuvastatin 40 mg (n=349 for IVUS analysis;
n=292 for QCA analysis)
Patients (≥18 years)
CAD, undergoing coronary
angiography
Target coronary artery: ≤50%
reduction in lumen diameter of
≥40 mm segment
Target segment for QCA: all
segments >25% at baseline
No cholesterol entry criteria

Visit:
Week:
Lipids Lipids
Tolerability
IVUS
QCA
Lipids
Tolerability
Lipids
Tolerability
Tolerability Tolerability Tolerability
1
–6
2
0
3
13
4
26
5
39
6
52
7
65
8
78
9
91
10
104
Eligibility
assessment


ASTEROID: Study Design
IVUS
QCA
Lipids
*P<0.001 for difference from baseline. Wilcoxon signed rank test
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Median atheroma volume in the
most diseased 10-mm
subsegment
Median normalized TAV
C
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

(
%
)

- 9.1%
*
*
- 6.8%
End Point Analysis:
Change in Key IVUS Parameters
n=319 n=346
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Example of Regression of Atherosclerosis with
Rosuvastatin in ASTEROID (measured by IVUS)
Sipahi I, Nicholls S, Tuzcu E,
Nissen S. Interpreting the
ASTEROID trial: Coronary
atherosclerosis can regress with
very intensive statin therapy.
Cleve Clin J Med, 2006; 73:937-
944.

Reprinted with
permission. Copyright
2006. Cleveland Clinic
Foundation. All rights reserved.

Diabetes Mellitus:
Effect of an HMG-CoA Reductase Inhibitor
Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37:117-25
Meta-analysis of 18,686 patients with DM randomized to treatment
with a HMG-CoA Reductase Inhibitor














A statin reduces adverse CV events in diabetics
Residual CVD Risk in Statin vs Placebo
Trials
4
HPS Collaborative Group. Lancet. 2002;360:7-22.
5
Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
6
Downs JR et al. JAMA. 1998;279:1615-1622.
1
4S Group. Lancet. 1994;344:1383-1389.
2
LIPID Study Group. N Engl J Med. 1998;339:1349-1357.
3
Sacks FM et al. N Engl J Med. 1996;335:1001-1009.

0
10
20
30
40
4S LIPID CARE HPS WOS AFCAPS /
TexCAPS
A LDL
N 4444 4159 20 536 6595 6605 9014
-35% -28% -29% -26% -25% -25%
Secondary High Risk Primary
P
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M
a
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C
H
D


E
v
e
n
t
s
,

%

4S
1
LIPID
2
CARE
3
HPS
4
WOSCOPS
5
AFCAPS/TexCAPS
6
Placebo
Statin
19.4
12.3
10.2
8.7
5.5
6.8
28.0
15.9
13.2
11.8
7.9
10.9
Many CHD Events Still Occur in Statin-Treated Patients
25-40% CVD Reduction Leaves High Residual Risk
Antioxidative
Activity
Antithrombotic
Activity
Potential Antiatherogenic Actions of HDL
Anti-infectious
Activity
Endothelial
Repair
Chapman MJ et al. Curr Med Res Opin. 2004;20:1253-1268.
Assmann G et al. Annu Rev Med. 2003;53:321-341.
Antiapoptotic
Activity
Reverse
Cholesterol
Transport
Cellular
Cholesterol
Efflux
Anti-inflammatory
Activity
Vasodilatory
Activity
HDL
Apo A-I
Apo A-II


Should High-Density Lipoprotein
Be a Target of Therapy?
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
1.4
MARS
MAAS
PLAC I LCAS
PLAC I
CCAIT
LCAS MAAS
MARS
ASTEROID
CCAIT
40 45 50
*
ASTEROID rosuvastatin MAAS simvastatin CCAIT lovastatin
MARS lovastatin LCAS fluvastatin PLAC I pravastatin
C
h
a
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i
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%

s
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p
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On-treatment HDL-C (mg/dL)
Change in Percent Diameter Stenosis
vs On-treatment HDL-C in QCA Trials
Placebo
Statin
*
Ballantyne CM, Nicholls S et al. Circulation 2008; Online
Should High-Density Lipoproteins Be a
Target of Therapy ?
 ATP III Guidelines on HDL-C: ―Current
documentation of risk reduction through controlled
clinical trials is not sufficient to warrant setting a
specific goal value for raising HDL-C‖ (Grundy SM et
al. Circulation. 2004;110:227-239)
 Failure of ACCORD, FIELD, AIM-HIGH and the
experience with torcetrapib and dalcetrapib have
raised doubts re: the value of raising HDL-C
 Still,
÷ The one best study of niacin effects on CVD (HPS-
2/THRIVE) is ongoing—results early in 2013
÷ Investigational CETP inhibitors greatly increase HDL-C
and might be shown to reduce CVD—clinical trials
ongoing, results after 2017
HDL-C Risk Factor vs Risk Marker?

Low HDL-C predicts high CVD Risk
High HDL-C predicts anti-atherogenic effects:
÷ Anti-inflammatory
÷ Antioxidant
÷ Antithrombotic
÷ Pro-endothelial
But clinical trials of HDL-C-raising agents so far
have failed to prove CVD benefit—suggesting
that HDL-C may be only a risk marker
• Smoking Cessation
− HDL-C levels are lower in smokers (by 7%-20%), and return
towards normal 1-2 months after smoking cessation
• Whole Food Plant Based Diet—dietary fiber blunts adverse
carb effect
• Weight Reduction
− For every 3 kg (7 lb) of weight loss, HDL-C levels increase
by 2-4%, but only after stabilization at new lower weight
• Exercise
− Aerobic exercise (40 min, 3-4 x weekly) may increase HDL-
C by 5-10%
Rössner S et al. Atherosclerosis. 1987;64:125-130.
Wood PD et al. N Engl J Med. 1988;319:1173-1179.
Ornish D et al. JAMA. 1998;280:2001-2007.
Lifestyle Modifications to Raise HDL-C
Levels
Cullen P et al. Eur Heart J. 1998;19:1632-1641.
Kokkinos PF et al. Arch Intern Med. 1995;155:415-420.
Kodama S et al. Arch Intern Med. 2007;167:999-1008.
Available Agents for HDL-C Raising
Agent HDL-C


Primary Use
Nicotinic acid 15-35% HDL ↑
Fibrates 5-20% TG ↓
Statins 5-15% LDL ↓
Prescr. Om-3* 2-10% TG ↓
Bile-acid resins* 2-5% LDL ↓
Ezetimibe* 1-3% LDL ↓
Pioglitazone* 5-20% Glucose ↓
Estrogens* 10-25% Hot flashes
o-blockers* 10-20% BPH
Alcohol* 5-15% Social, etc.
*Lacking FDA-approved indication for HDL-raising.
Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174.
Insull W et al. Mayo Clin Proc. 2001;76:971-982.
McKenney JM et al. Pharmacother. 2007;27:715-728.
Risk Reduction for CHD Events
As a Function of Changes in TC, LDL-C, and
HDL-C
*4S, CARE, LIPID, WOSCOPS
**HELSINKI, VA-HIT,AFCAPS/TexCAPS
PERCENT CHD EVENT
CHANGE RATE
Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD)
C
H
D

D
e
a
t
h


o
r

N
o
n
f
a
t
a
l

M
I

(
%
)

Placebo
5.9
Fenofibrate
9
6
3
0
5.2
P=0.16
11% RRR
9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo
for 5 years









A fibrate does not provide significant additional benefit* in diabetics
Source: Keech A et al. Lancet 2005;366:1849-61
*Unadjusted for concomitant statin use
CHD=Coronary heart disease, MI=Myocardial
infarction, RRR=Relative risk reduction
Fibrate Evidence:
Primary Prevention
ACCORD Lipid Study Results
(NEJM 2010; 362: 1563-74)
5518 patients with type 2 DM treated with open
label simvastatin randomly assigned to
fenofibrate or placebo and followed for 4.7
years.
Annual rate of primary outcome of nonfatal MI,
stroke or CVD death 2.2% in fenofibrate group
vs. 1.6% in placebo group (HR=0.91, p=0.33).
Pre-specified subgroup analyses showed
possible benefit in men vs. women and those
with high triglycerides and low HDL-C.
Results support statin therapy alone to reduce
CVD risk in high risk type 2 DM patients.
Fibrate Evidence:
Primary and Secondary Prevention
Action to Control Cardiovascular Risk in Diabetes
(ACCORD) Lipid Trial
5,518 diabetic patients on statin therapy randomized to fenofibrate
(160 mg) or placebo for 4.7 years










On a background of statin therapy, a fibrate does not reduce CV events
in diabetics
C
V

d
e
a
t
h
,

n
o
n
f
a
t
a
l

s
t
r
o
k
e

o
r

n
o
n
f
a
t
a
l

M
I

(
%
/
y
e
a
r
)

Placebo
2.4
Fenofibrate
3
2
1
0
2.2
P=0.32
8% RRR
Source: ACCORD study group. NEJM 2010;Epub ahead of print
CV=Cardiovascular, MI=Myocardial infarction,
RRR=Relative risk reduction


Is Niacin Useful in Low HDL-C?
HATS: Percent Change in Stenosis
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
C
h
a
n
g
e

(
%
)

*P = 0.16 for comparison with placebo;

P < 0.001;

P = 0.004.
HATS = HDL-Atherosclerosis Treatment Study.

Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.
Placebo Antioxidant Simvastatin/ Simvastatin /
Vitamins* Niacin

Niacin/
Antioxidants

Simvastatin-niacin
97%
All placebos
76%
RR = 0.10
P = 0.03
0 1 2 3
0
70
80
90
100
HATS = HDL-Atherosclerosis Treatment Study.
Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.
HATS: Patients Free of Events
P
a
t
i
e
n
t
s

F
r
e
e

o
f

E
v
e
n
t
s

(
%
)

Years
Study
Treatme
nt
n/N
Control
n/N
Peto OR
95% Cl
Peto OR
95% Cl
ARBITER-6-
HALTS
2/187 9/176
0.25 (0.08,
0.84)
Guyton JR et al 1/676 1/272
0.35 (0.02,
7.56)
AFREGS 0/71 1/72
0.14 (0.00,
6.92)
ARBITER-2 2/87 2/80
0.92 (0.13,
6.65)
HATS 1/38 5/38
0.24 (0.05,
1.26)
UCSF_SCOR 0/48 1/49
0.14 (0.00,
6.96)
STOCKHOLM 72/279 100/276
0.61 (0.43,
0.88)
CLAS 1/94 5/94
0.25 (0.05,
1.29)
CDP 287/1119 839/2789
0.81 (0.69,
0.94)
Total
Test for heterogeneity: P = 0.24, I
2
=
23.0%
Test for overall effect: P <0.0001


0.75 (0.65,
0.86)

Subtotal excluding CDP
0.53 (0.38,
0.73)
0.1 0.2 0.5 1 2 5 10
Log scale
Meta-Analysis: Effects of Nicotinic Acid
Pre-AIM-HIGH Trials: Major Coronary Events
Many of these trials were tests of drug combinations that included niacin.
Bruckert E et al. Atherosclerosis. 2010;210:353-361.

AIM-HIGH
Design
 Purpose: ―Rigorous test of the HDL hypothesis…‖
÷ (not designed to be a test of niacin)
 Subjects: n=3414 men/women (85%/15%) w/ prior
CVD event and HDL-C 35 (<42/53) LDL-C 74
(algorithm), TG 163 (100-400) [median (range)]
 Randomized Therapy
÷ Extended-release niacin (1500-2000 mg hs) vs
÷ ―Placebo‖ (immediate-release niacin 100-150 mg hs)
 Open-label titration/addition (keep LDL-C in 40-80
mg/dL)
÷ Simvastatin 5-80 mg/d
÷ Ezetimibe 10 mg/d + extended release niacin (1500-
2000 mg)
AIM-HIGH Investigators. N Engl J Med. 2001;365:2255-267.
AIM-HIGH Investigators. Am Heart J. 2011;161:471-477.e2.
Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.
AIM-HIGH — Results
HDL-C at Baseline and Follow-up
1
o
Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS,
hospitalization for coronary or cerebrovascular revascularization
Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.
AIM-HIGH — Results
Primary Outcome
Fate of Niacin Beyond AIM-HIGH: HPS2-
THRIVE : December 2012 Update
HPS2-THRIVE evaluated extended-release
niacin/laropiprant plus statin therapy versus
statin therapy alone in patients at high risk for
cardiovascular events
HPS2-THRIVE did not reach the primary
endpoint to reduce coronary deaths, non-fatal
heart attacks, strokes, or revascularizations
 This finding, supportive of AIM-HIGH, suggests
that niacin may not provide additional benefit to
reduce CVD risk when patients are well-treated
with statins



Emerging HDL-C Therapies
CETP Antagonism
Role of CETP in Atherosclerosis
 Human CETP deficiency is usually associated with marked ↑ in HDL-
C
 CETP activity is inversely correlated with plasma HDL-C
 Decreasing CETP activity has consistently inhibited atherosclerosis
in animal models

Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167.
Contacos C et al. Atherosclerosis. 1998;141:87-98.
Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28:148-154.






LIVER PERIPHERAL TISSUE
CE
TG
Bile
Foam
cells
RCT
HDL
ABC-A1
VLDL LDL
PLASMA
LDL-R
ABC-G1
Free
cholesterol
CETP
Athero-
sclerosis
LDL
Barter et al. N Engl J Med. 2007;357(13):2109-2122.
http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc.
http://www.ama-assn.org/ama1/pub/upload/mm/365/torcetrapib.doc.
Qiu X et al. Nat Struct Mol Biol. 2007;14(2):106-113.

http://www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.
http://www.roche.com/media/media_releases/med-cor-2012-05-07.htm.
*Dalcetrapib development stopped May 7, 2012 due to lack of efficacy in the
Dal-Outcomes CVD endpoint trial.
CETP Inhibitors: 2 Down, 2 Remain
CETP
Evacetrapib
↑CVD (25%)
but OK HDL
function
(off-target eff.?)
*No ↓CVD,
but OK HDL
function, +/- anti
athero?
--------------------↑HDL-C----------------------
~80% ~80% ~138% ~30%
Lipid Effects of CETP
Inhibitors/Modulators
% Change from Baseline
CETP Agent
Dose
(mg/day)
HDL-C
(%)
LDL-C
(%)
TG (%)
Torcetrapib
60 61 -24 -9
Anacetrapib
100 138 -40 -7
Evacetrapib
500 129 -36 -11
Dalcetrapib
600 31 -2 -3
Adapted from Cannon C et al. JAMA. 2011;306:2153-2155.
Nicholls SJ et al. JAMA. 2011;306:2099-2109.
Is the toxicity of torcetrapib related to the mechanism or the molecule?
Atorvastatin only
Torcetrapib plus atorvastatin
0 90 180 270 360 450 540 630 720 810
Days After Randomization
P
a
t
i
e
n
t
s

W
i
t
h
o
u
t

E
v
e
n
t

(
%
)

100
98
96
94
92
90
0
Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

Torcetrapib: Increased Cardiovascular and
Non-cardiovascular Morbidity and Mortality
HR = 1.25
P = 0.0001
Torcetrapib Caused Off-target
Hyperaldosteronism
 Torcetrapib arm of ILLUMINATE trial showed significant:
1
÷ ↑ Systolic Blood Pressure:
- Mean ↑5.4 mmHg
- >15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo
arm, P<0.001)
÷ ↓ serum potassium
÷ ↑ serum bicarbonate
÷ ↑ serum sodium
÷ ↑ serum aldosterone
 Inverse relationship of CVD and on-Rx-HDL-C preserved
 Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of
torcetrapib, not related to CETP inhibition
1,2
1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.
2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.
dal-OUTCOMES Results: Isolated ↑HDL-C
L
D
L

C
h
o
l
e
s
t
e
r
o
l

(
m
g
/
d
L
)

H
D
L

C
h
o
l
e
s
t
e
r
o
l

(
m
g
/
d
L
)

Schwartz GG et al.
N Engl J Med. 2012
Nov 5.
[Epub ahead of
print].
No. at risk
Placebo 7907 7685 7498 7272 6959 6436 3650
Dalcetrapib 7910 7663 7402 7196 6871 6333 3599
No. at risk
Placebo 7907 7679 7473 7265 6947 6427 3640
Dalcetrapib 7910 7657 7382 7191 6863 6324 3591
Months
dal-OUTCOMES Results: No ↓CVD
Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].
Year
C
u
m
u
l
a
t
i
v
e

I
n
c
i
d
e
n
c
e

o
f

P
r
i
m
a
r
y

O
u
t
c
o
m
e


(
%

o
f

p
a
t
i
e
n
t
s
)

No. at risk
Placebo 7933 7386 6551 1743
Dalcetrapib 7938 7372 6495 1736
dal-OUTCOMES Results: HDL STILL Functional
Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].
Change in HDL Cholesterol (mg/dL) from Baseline to Month
1, According to Quintile
A
n
n
u
a
l
i
z
e
d

E
v
e
n
t

R
a
t
e

(
%
)

Revisiting the HDL Hypothesis
Where do we go Next?

Residual CVD risk exists despite intense statin
monotherapy
Low HDL-C predicts high CVD risk; high HDL-C is
protective
Existing HDL raising therapies have inconsistent
effects
Clinical trials have not yet answered the following:
÷ Is HDL a causal factor or a biomarker of risk?
÷ Does raising HDL-C reduce CVD risk?
Investigational drugs to raise HDL-C and reduce
CVD risk
Continued need for multifactorial approaches to
reduce CVD risk
Current Investigational Approaches to
Reduce Residual CVD Risk via Enhanced
HDL, etc.
 Additional CETP inhibitors: anacetrapib, evacetrapib
 Apolipoprotein A1 (Apo A1) Milano; Apo A1 agonist
 Delipidated HDL; rHDL
 Selective LXRβ (liver X receptor) agonist
DMHCA; GW 3965
 PPAR (peroxisome proliferator-activated receptor α/γ
agonist
aleglitazar, muraglitazar, tesaglitazar
 DPP-4 (dipeptidyl peptidase-4) antagonist
alogliptin, linagliptin, saxagliptin, sitagliptin
 MTP (microsomal transport protein) antagonist
Lp-PLA
2
and vascular disease
LpPLA2 Studies Collaboration (2010) Lancet 375; 1536-1544
Effects of Lp-PLA2 inhibition by darapladib
in diabetic, hypercholesterolemic pigs
Wilensky et al (2008) Nature Medicine (in press)
Novel anti-atherosclerotic agents
Darapladib in animal models and clinical trials
STABILITY Stabilization of
Atherosclerotic Plaque by Initiation
of Darapladib Therapy
Estimated enrolment 15,500
• Darapladib vs placebo in well
treated patients with CHD plus
other risk.
• 1ary endpoint major coronary
event

SOLID – TIMI52 Stabilization
of plaques using darapladib.
• Incidence of major coronary
events in patients with ACS
•Darapladib 160 mg vs placebo
started within 30 days of index
ACS event.
NCEP ATP III: Evaluation—
Major Risk Factors for CAD
Age (men >45 y; women >55 y)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
Cigarette smoking
Hypertension (BP >140/90 mm Hg or
antihypertensive medication)
HDL-C <40 mg/dL
Family history of premature CAD
÷ <55 y in first-degree male relative
÷ <65 y in first-degree female relative
Revised ATP III (AHA/NHLBI) Metabolic Syndrome
Definition 2005
*Diagnosis is established when >3 of these risk factors are present.

Abdominal obesity is more highly correlated with metabolic risk factors than is |BMI.

Some men develop metabolic risk factors when circumference is only marginally
increased.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-
2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub).
<40 mg/dL
<50 mg/dL or Rx for ↓ HDL
Men
Women
>102 cm (>40 in)
>88 cm (>35 in)
Men
Women
>100 mg/dL or Rx for ↑ glucose Fasting glucose
>130/>85 mm Hg or on HTN Rx Blood pressure
HDL-C
>150 mg/dL or Rx for ↑ TG TG
Abdominal obesity


(Waist circumference

)
Defining Level Risk Factor
NCEP ATP III: Evaluation—
Need for Framingham Calculation
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
No >20% CAD or CAD risk
equivalent
Yes 0%-10%
>2 RF
No <10% s1 RF
Need for
Framingham
Calculation

10-Year Risk
for CAD

Risk Profile
Yes 10%-20%
NCEP ATP III: Evaluation—
CAD Risk Equivalents
Diabetes
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
Atherosclerotic disease
÷ Peripheral artery disease
÷ Abdominal aortic aneurysm
÷ Symptomatic carotid artery disease
CAD 10-year risk >20%
Note: Risk estimates were derived from the experience of the Framingham Heart Study,
a predominantly Caucasian population in Massachusetts, USA.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
Assessing CHD Risk in Men
Step 1: Age
Years Points
20-34 -9
35-39 -4
40-44 0
45-49 3
50-54 6
55-59 8
60-64 10
65-69 11
70-74 12
75-79 13
Step 2: Total Cholesterol

TC Points at Points at Points at Points
at Points at
(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age
70-79
<160 0 0 0 0 0
160-199 4 3 2 1 0
200-239 7 5 3 1 0
240-279 9 6 4 2 1
>280 11 8 5 3 1
HDL-C
(mg/dL) Points
>60 -1
50-59 0
40-49 1
<40 2
Step 3: HDL-Cholesterol
Systolic BP Points Points
(mm Hg) if Untreated if Treated
<120 0 0
120-129 0 1
130-139 1 2
140-159 1 2
>160 2 3
Step 4: Systolic Blood Pressure
Step 5: Smoking Status
Points at Points at Points at Points
at Points at
Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age
70-79
Nonsmoker 0 0 0 0 0
Smoker 8 5 3 1 1
Age
Total cholesterol
HDL-cholesterol
Systolic blood pressure
Smoking status
Point total
Step 6: Adding Up the Points
Point Total 10-Year Risk Point Total 10-Year
Risk
<0 <1% 11 8%
0 1% 12 10%
1 1% 13 12%
2 1% 14 16%
3 1% 15 20%
4 1% 16 25%
5 2% >17 >30%
6 2%
7 3%
8 4%
9 5%
10 6%
Step 7: CHD Risk
ATP III Framingham Risk Scoring
© 2001, Professional Postgraduate Services
®

www.lipidhealth.org
Point Total 10-Year Risk Point Total 10-Year
Risk
<9 <1% 20 11%
9 1% 21 14%
10 1% 22 17%
11 1% 23 22%
12 1% 24 27%
13 2% >25 >30%
14 2%
15 3%
16 4%
17 5%
18 6%
19 8%
Assessing CHD Risk in Women
Note: Risk estimates were derived from the experience of the Framingham Heart Study,
a predominantly Caucasian population in Massachusetts, USA.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
Step 1: Age
Years Points
20-34 -7
35-39 -3
40-44 0
45-49 3
50-54 6
55-59 8
60-64 10
65-69 12
70-74 14
75-79 16

TC Points at Points at Points at Points
at Points at
(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age
70-79
<160 0 0 0 0 0
160-199 4 3 2 1 1
200-239 8 6 4 2 1
240-279 11 8 5 3 2
>280 13 10 7 4 2
HDL-C
(mg/dL) Points
>60 -1
50-59 0
40-49 1
<40 2
Step 3: HDL-Cholesterol
Systolic BP Points Points
(mm Hg) if Untreated if Treated
<120 0 0
120-129 1 3
130-139 2 4
140-159 3 5
>160 4 6
Step 4: Systolic Blood Pressure
Step 5: Smoking Status
Points at Points at Points at Points
at Points at
Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age
70-79
Nonsmoker 0 0 0 0 0
Smoker 9 7 4 2 1
Age
Total cholesterol
HDL-cholesterol
Systolic blood pressure
Smoking status
Point total
Step 6: Adding Up the Points
Step 7: CHD Risk
Step 2: Total Cholesterol
ATP III Framingham Risk Scoring
© 2001, Professional Postgraduate Services
®

www.lipidhealth.org
hs-CRP Adds to Predictive Value of TC:HDL Ratio in
Determining Risk of First MI
0.0
1.0
2.0
3.0
4.0
5.0
High Medium Low Low
Medium
High
Total Cholesterol:HDL Ratio
Ridker et al, Circulation. 1998;97:2007–2011.
R
e
l
a
t
i
v
e

R
i
s
k

JUPITER
Why Consider Statins for Low LDL, high hsCRP Patients?
However, while intriguing and of potential public health importance, the
observation in AFCAPS/TexCAPS that statin therapy might be effective
among those with elevated hsCRP but low cholesterol was made on a
post hoc basis. Thus, a large-scale randomized trial of statin therapy was
needed to directly test this hypotheses.

Ridker et al, New Engl J Med 2001;344:1959-65
Low LDL, Low hsCRP

Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.0 0.5
[A]
[B]
Low LDL, Low hsCRP

Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.0 0.5
AFCAPS/TexCAPS Low LDL Subgroups
RR
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
JUPITER
Trial Design
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
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT
5
) = 25
- 44 %
0 1 2 3 4
0
.
0
0

0
.
0
2

0
.
0
4

0
.
0
6

0
.
0
8

C
u
m
u
l
a
t
i
v
e

I
n
c
i
d
e
n
c
e

Number at Risk
Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
Ridker et al NEJM 2008
JUPITER population – high CRP (>2mg/l), low LDL
Dual Target Analysis: LDL-C <70 mg/dL, hsCRP <2 mg/L
LDL >70 mg/dL
and / or
hsCRP >2 mg/L
HR 0.64 (0.49-0.84)
LDL <70 mg/dL
and hsCRP <2 mg/L
HR 0.35 (0.23-0.54)
placebo HR 1.0
(referent)
P <0.0001
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
C
u
m
u
l
a
t
i
v
e

I
n
c
i
d
e
n
c
e

Number at Risk
Follow-up (years)
rosuvastatin
placebo
7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145
7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168
Ridker PM et al. Lancet 2009;373:1175–1182
s 1 RF
> 2 RFs
equivalent
CAD or
CAD risk
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
Risk
Category
<160
<130
<100
<130
LDL - C
Goal
(mg/dL)
> 160
> 130
> 100
> 130
LDL - C Level
to Initiate
TLC (mg/dL)
LDL - C Level
to Initiate
Drug Therapy
(mg/dL)
> 190
> 160
> 130
> 130
(10-year risk
0%-10%)
(10-year risk
10%-20%)
NCEP ATP III Guidelines: Treatment
Statins in ACS - Guidelines
• Who - Initiate therapy regardless of baseline LDL.
• When – Pre-discharge; but no difference in benefit
when initiated immediately or days post event (ESC
<4 days).
• What – Evidence base is for high dose statin (but
not 80mg simvastatin).
• Goal - <70 mg/dl (2.0 mmol/l) LDL cholesterol.
ACC/ AHA 2007 in JACC (2008) 51; 210-47 ESC 2007 in Eur Heart J (2007) 28; 1598-1660
Lipid Management Goal: Persons
with Pre-existing CHD

LDL-C should be less than 100 mg/dL


Further reduction to LDL-C to < 70 mg/dL is
reasonable
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
IIa IIa IIa
IIb IIb IIb
III III III
*Non-HDL-C = total cholesterol minus HDL-C
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
IIa IIa IIa
IIb IIb IIb
III III III
If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*
s1 RF <190

>2 RFs
(CAD risk s20%) <160

CAD or
CAD risk equivalent <130
(CAD risk >20%)
NCEP ATP III: Setting Goals—
Secondary–Non-HDL-C

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
Risk Category Non–HDL-C Goal (mg/dL)
(Patients With TG >200)
Level (mg/dl) Classification
<200 Desirable
200-239 Borderline High
>240 High
Level (mg/dl) Classification
>40 Minimum goal*
40-50 Desired goal*
>50 High
Level (mg/dl) Classification
<150 Normal
150-199 Borderline High
200-499 High
>500 Very High
Total Cholesterol HDL-Cholesterol
Triglyceride
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-97

ATP III Classification of Other Lipoprotein Levels
*These goals apply to men. For women, the minimum goal is >50 mg/dL
HDL=High density lipoprotein
NCEP ATP III Guidelines: Treatment
Therapeutic
Lifestyle Change (TLC)

Improve diet
Weight reduction
Physical activity
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
Pharmacologic
Treatment

Statins (HMG-CoA
reductase inhibitors)
Fibrates
Niacin
Bile acid sequestrants
Lipid Management
Recommendations

Start dietary therapy (<7% of total calories as saturated
fat and <200 mg/d cholesterol)

Adding plant stanol/sterols (2 gm/day) and viscous fiber
(>10 mg/day) will further lower LDL

Promote daily physical activity and weight
management.

Encourage increased consumption of omega-3 fatty
acids in fish or 1 g/day omega-3 fatty acids in capsule
form for risk reduction.
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
I I I
IIa IIa IIa
IIb IIb IIb
III III III
IIa IIa IIa
IIb IIb IIb
III III III
I I I IIa IIa IIa
IIb IIb IIb
III III III
I I I IIa IIa IIa
IIb IIb IIb
III III III
I I I IIa IIa IIa
IIb IIb IIb
III III III
IIa IIa IIa
IIb IIb IIb
III III III
For all patients
Therapeutic Lifestyle Changes
Nutrient Composition of TLC Diet
Nutrient Recommended Intake
 Saturated fat Less than 7% of total calories
 Polyunsaturated fat Up to 10% of total calories
 Monounsaturated fat Up to 20% of total calories
 Total fat 25–35% of total calories
 Carbohydrate 50–60% of total calories
 Fiber 20–30 grams per day
 Protein Approximately 15% of total calories
 Cholesterol Less than 200 mg/day
 Total calories (energy) Balance energy intake and expenditure
to maintain desirable body weight
Possible Benefits From Other Therapies
Therapy Result
• Soluble fiber in diet (2–8 g/d)
(oat bran, fruit, and vegetables)

• Soy protein (20–30 g/d)

• Stanol esters (1.5–4 g/d)
(inhibit cholesterol absorption)

• Fish oils (3–9 g/d)
(n-3 fatty acids)
+ LDL-C 1% to 10%


+ LDL-C 5% to 7%

+ LDL-C 10% to 15%


+ Triglycerides 25% to 35%

Jones PJ. Curr Atheroscler Rep. 1999;1:230-235.
Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214.
Rambjor GS et al. Lipids. 1996;31:S45-S49.
Ripsin CM et al. JAMA. 1992;267:3317-3325.
Dietary Adjuncts
TLC for patients with LDL-C = 160
Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17:375-382.
Jenkins DJ et al. Curr Opin Lipidol 2000;11:49-56.
Cato N. Stanol meta-analysis. Personal communication, 2000.
Dietary Component LDL-C + (mg/dL)
Low saturated fat/dietary cholesterol –12
Viscous fiber (10–25 g/d) –8
Plant stanols/sterols (2 g/d) –16
Total –36 mg/dl
Moderate physical activity at least 30-60 minutes 5
days a week or longer will help to raise HDL-C, lower
total and LDL-C, lower TG, lower glucose, insulin,
and blood pressure levels.
Questran
®
Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing
information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ®
Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information,
Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing
Information; Zetia ® Prescribing Information.
Effect of Lipid-modifying Therapies
TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein,
TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.
Therapy TC LDL HDL TG
Patient
tolerability
Bile acid
sequestrants
+ 7-10% + 10-18% 3% Neutral or Poor
Nicotinic acid + 10-20% + 10-20% 14-35% + 30-70%
Poor to
reasonable
Fibrates
(gemfibrozil)
+ 19% + 4-21% 11-13% + 30% Good
Statins* + 19-37% + 25-50% 4-12% + 14-29% Good
Ezetimibe + 13% + 18% 1% + 9% Good
When LDL-lowering drug therapy
is employed in high-risk or
moderately high risk patients,
intensity of therapy should be
sufficient to achieve a 30–40%
reduction in LDL-C levels.
Effect of Statin Therapy on LDL-C
Levels: ―The Rule of 6‖
Illingworth DR. Med Clin North Am. 2000;84:23-42.
37
19
35
27
28
18
12
12
6
12
0 10 20 30 40 50 60
Atorvastatin 10/80
Fluvastatin 20/80
Simvastatin 20/80
Pravastatin 20/40
Lovastatin 20/80
Reduction of LDL Cholesterol (%)
Starting dose LDL-C
Highest
recommended dose
Atorvastatin
Pravastatin
Rosuvastatin

Simvastatin
10 mg 20 mg 40 mg 80 mg
Dose
*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg
**P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg
† P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg
1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160.
2.Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.
*
**

–60
–50
–40
–30
–20
–10
0
M
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F
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i
n

L
D
L
-
C

(
±
S
E
)

Percentage Change From Baseline in
LDL-C at Week 6 by Dose (ITT)
1,2
Grundy et al. Circulation. 2004;110:227-239.
Doses of Statins Required to Attain
30-40% Reduction of LDL-C
Dose, mg/d
LDL Reduction,
%
Atorvastatin 10 39
Lovastatin 40 31
Pravastatin 40 34
Simvastatin 20-40 35-41
Fluvastatin 40-80 25-35
Rosuvastatin 5-10 39-45
Source: Kashani A et al. Circulation 2006;114:2788-97
• 1.4% incidence of elevated hepatic
transaminases (1.1% incidence in
control arm)
• Dose-dependent phenomenon that is
usually reversible
• 15.4% incidence of myalgias*
(18.7% incidence in control arm)
• 0.9% incidence of myositis (0.4%
incidence in control arm)
• 0.2% incidence of rhabdomyolysis
(0.1% incidence in control arm)
74,102 subjects in 35 randomized clinical trials with statins
*The rate of myalgias leading to discontinuation of atorvastatin in the TNT
trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively.
HMG-CoA Reductase Inhibitor:
Adverse Effects
Hepatocyte
Skeletal myocyte
Why combination therapy?
Few patients achieve LDL-C goal on
monotherapy
Uptitration of dosage is rare
LDL-C goals are getting more aggressive
High-dose statins increase risk of side effects
Can address mixed dyslipidemia (e.g., few pts
achieve adequate control of HDL-C and
triglycerides on monotherapy)
Options for Patients who Fail to Reach
LDL-C Goal on Statin Monotherapy
• Niacin
• Bile acid sequestrant
• Cholesterol absorption inhibitor
Addition of:
Pharmacologic Therapy: Niacin
Reduces HDL catabolism and VLDL production
Primarily used to treat low HDL-C (15%-35%|)
and elevated TG (20%-50% +)
LDL-C + 5%-25%
Side effects
÷ Hepatotoxicity, hyperglycemia, hyperuricemia,
upper GI distress, flushing, itching
Contraindicated in patients with liver disease,
gout, peptic ulcer
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
M
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c
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B
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Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105
500
HDL-C
LDL-C
TG
–9%
–14%
–22%
–21%
–17%
30%
30%
26%
22%
15%
10%
–28%
–35%
–44%
–39%
–11%
–5%
1000 1500 2000 2500 Dose (mg) 3000
Nicotinic Acid Evidence:
Effect on Lipid Parameters
-50
-40
-30
-20
-10
0
10
20
30
HDL-C=High density lipoprotein cholesterol, LDL-C=Low
density lipoprotein cholesterol, TG=Triglyceride
Bile Acid Sequestrants
Major actions
÷ Reduce LDL-C 15%-30%
÷ Raise HDL-C 3%-5%
÷ May increase TG
Side effects
÷ GI distress/constipation
÷ Decreased absorption of other drugs (1st generation)
Contraindications
÷ Dysbetalipoproteinemia
÷ Elevated TG (especially >400 mg/dL)
New Bile Acid Sequestrant:
Colesevelam
Lower dose for effect
Fewer GI complaints than with other bile
acid sequestrants
Reduces absorption of |-carotene
Requires 4-6 tablets/day
Davidson et al. Expert Opin Investig Drugs. 2000;9:2663.
Insull et al. Mayo Clin Proc. 2001;76:971.
*P<0.001 vs placebo.

P=0.04 vs placebo.
5
-1
0
10
3
-15
-20
-15
-10
-5
0
5
10
15
%

C
h
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g
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f
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m

b
a
s
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l
i
n
e

a
t

w
k

2
4

TG HDL-C LDL-C
*

Placebo (n=88)
Colesevelam 3.8 g/d (n=95)
Colesevelam Monotherapy: Efficacy
Pharmacologic Therapy: Fibrates
Inhibit hepatic TG production and increase HDL production
Used to treat elevated TG (20%-50% +)
and low HDL-C (10%-20% |)
Variable effect on LDL-C
Side effects
÷ Dyspepsia, gallstones, myopathy
÷ Increased with statins
Contraindicated in patients with severe renal or hepatic
disease
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486.
Limitations of Current
Intestinal-Acting Agents
Bile acid sequestrants
÷ Noncompliance
÷ GI tolerability
÷ Reduced absorption of lipid-soluble vitamins
÷ May increase TG in patients with hypertriglyceridemia
Plant stanol and sterol esters
÷ Lack of selectivity
÷ Some patients may find difficult to incorporate into
diet
÷ May reduce absorption of lipid-soluble vitamins

Ezetimibe —
Localizes at Brush Border of Small Intestine
Ezetimibe, a selective cholesterol absorption
inhibitor, localizes and appears to act at the
brush border of the small intestine and inhibits
cholesterol absorption
This results in
÷ A decrease in the delivery of intestinal cholesterol to
the liver
÷ A reduction of hepatic cholesterol stores and an
increase in clearance of cholesterol from the blood
Ezetimibe and Statins
Complementary Mechanisms
Ezetimibe reduces the delivery of cholesterol to the liver
Statins reduce cholesterol synthesis in the liver
The distinct mechanism of ezetimibe is complementary to
that of statins
The effects of ezetimibe, either alone or in addition to a
statin, on cardiovascular morbidity or mortality have not
been established
Knopp RH. N Engl J Med. 1999;341:498–511.
M
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Placebo
(n = 11)
-30
-20
-10
0
SIMVA 10 mg
(n = 12)
SIMVA 10+
EZE 10 mg
(n = 11)
-34.9*
-51.9*†
-3.2
-40
-50
-60
Coadministration:
Simvastatin + Ezetimibe
*P < 0.01 vs placebo
†P < 0.01 vs simvastatin 10 mg
Stein, E. Eur Heart J. 2001;3(suppl E):E14.
17%
%

R
e
d
u
c
t
i
o
n

Triglyceride
*P<0.05
-10
-20
-30
-40
-50
0
-46*
-21*
Total
Cholesterol
Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731
27 patients with hypertriglyceridemia and low HDL-C treated
with e-3 fatty acid (4 grams/day) for 7 months
e-3 Fatty Acids Evidence:
Effect on Lipid Parameters
HDL-C=High-density lipoprotein cholesterol
Source: Yokoyama M et al. Lancet. 2007;369:1090-8
Japan Eicosapentaenoic acid Lipid Intervention
Study (JELIS)
*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG
Years
e-3 Fatty Acids Evidence:
Primary and Secondary Prevention
18,645 patients with hypercholesterolemia randomized to EPA (1800 mg)
with a statin or a statin alone for 5 years









e-3 fatty acids provide CV benefit, particularly in secondary prevention
CV=Cardiovascular, EPA=Eicosapentaenoic acid
e-3 Fatty Acids Evidence:
Secondary Prevention
**p<0.05
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
7.0%
8.0%
e-3 Fatty Acids
Placebo
Source: Burr ML et al. Lancet 1989;2:757-761
Diet and Reinfarction Trial (DART)
A
l
l

c
a
u
s
e

m
o
r
t
a
l
i
t
y

(
%
)

*Corresponds to 2.5 grams of EPA (PUFA)
EPA=Eicosapentaenoic acid, MI=Myocardial infarction
2,033 men with a history of a MI randomized to a diet of reduced fat with an
increased ratio of polyunsaturated to saturated fat, increased fatty fish
intake*, or increased fiber intake for 2 years








e-3 fatty acids reduce all cause mortality** after a MI
11,324 patients with a history of a MI randomized to e-3 polyunsaturated
fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years










e-3 fatty acids provide significant CV benefit after a MI
Source: GISSI Investigators. Lancet 1999;354:447-455
e-3 Fatty Acids Evidence:
Secondary Prevention
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
miocardico (GISSI-Prevenzione)
CV=Cardiovascular, MI=Myocardial infarction, NF=Non-
fatal, PUFA=Polyunsaturated fatty acids
P
e
r
c
e
n
t

o
f

p
a
t
i
e
n
t
s

P=0.048 P=0.053 P=0.023 P=0.008
stroke stroke
0
2
4
6
8
10
12
14
16
Death,
NF MI,
NF stroke
(2 way)
CV
death,
NF MI,
and NF
Death,
NF MI,
NF stroke
(4 way)
CV
death,
NF MI,
and NF
e-3 PUFA
Placebo
3,827 patients 3-14 days following a MI randomized to e-3 fatty acids (460
mg EPA + 380 mg DHA) or placebo for 1 year







e-3 fatty acids provide no benefit following a MI in those with high
utilization of risk reducing therapies

OMEGA Trial
Source: Senges J et al. Presented at the Annual Scientific Sessions of the
American College of Cardiology, March 2009, Orlando, FL
Placebo
8.8
Fatty acids
12
8
4
0
10.4
P=0.10
R
a
t
e

o
f

r
e
i
n
f
a
r
c
t
i
o
n
,

s
t
r
o
k
e
,

o
r

d
e
a
t
h
*

(
%
)

DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic
acid, MI=Myocardial infarction
*This is a secondary endpoint
e-3 Fatty Acids Evidence:
Secondary Prevention
CONCLUSIONS
 Many persons with normal total or LDL-C levels still
suffer CHD events.
 While statin-based clinical trials significantly reduce risk
of CHD, residual risk still exists.
 Non-HDL-C, which reflects all the atherogenic lipid
fractions, appears to be a stronger predictor of CHD
events than LDL-C.
 The measurement of non-HDL-C and its use as a
secondary therapeutic target is warranted to better
address residual CHD risk.
 Lifestyle therapies as well as pharmacologic
approaches, particular combination therapy with statins
and other agents, are important for optimizing the entire
lipid profile.