Treating Lipid Abnormalities Beyond LDL - Washington Hospital ...

Treating Lipid Abnormalities
Beyond LDL
H. Bryan Brewer, Jr., MD
Cardiovascular Research Institute
Medstar Research Institute
Washington, DC

Disclosure
• Consulting Agreements: Merck & Co.; Pfizer Inc;
Sanofi; AstraZeneca; Roche; Genentech; InfraReDx
• Speakers’ Bureau/Honorarium Agreements: Merck &
Co.; Roche; Genentech; Pfizer Inc; Sanofi;
AstraZeneca; InfraReDx; HDL Therapeutics
• Financial Interests/Stock Ownership: Medicines
Company; InfraReDx, HDL Therapeutics

THE PYRAMID OF CVD
TRIALS
Very high cholesterol
with CHD or MI
Moderately high cholesterol
in high-risk CHD or MI
Normal Cholesterol
with CHD or MI
High cholesterol with
NO CHD or MI
No history of CHD or MI, average TG
and LDL-C, but below average HDL-C
Comparison of coronary clinical events with
LDL reduction by pravastatin and atorvastatin
No history of CVD with Normal LDL and Increased CRP
4S
PLAC I/II, KAPS, REGRESS
CARE
WOSCOPS
AFCAPS/TexCAPS
PROVE -IT
JUPITER
HPS Collaborative Group. Lancet. 2002;360(9326):7-22; LaRosa JC, et al. N Engl J Med. 2005;352(14):1425-1435; 4S Group. Lancet.
1994;344(8934):1383-1389; Sacks FM, et al. N Engl J Med. 1996; 335(14):1001-1009; Shepherd J, et al. N Engl J Med. 1995; 333(20):1301-
1307; Downs JR, et al. JAMA. 1998;279(20):1615-1622; Cannon CP, et al. N Engl J Med. 2004;350(15):1495-1504; Circulation.

Percent Decrease in Cardiovascular Risk
RESIDUAL CARDIOVASCULAR RISK IN STATIN TREATED
PATIENTS
0
25
50
75
100
4S WOS CARE HPS
LDL
62 mg/dL
Prove
It
LDL
77 mg/dL
TNT
CTT Meta
Analysis
LDL
54 mg/dL
Jupiter
30% 31% 24% 24% 16% 24% 24% 56%
Percent Decrease in Cardiovascular Risk
70% 69% 76% 76% 84% 76% 76% 44%
Percent Residual Risk in Cardiovascular Risk

UNMET CLINICAL
NEED
TREATMENT OF THE
RESIDUAL
CARDIOVASCULAR
DISEASE

HDL: The Next Frontier in the Treatment
of the Residual Cardiovascular Risk in
Statin Treated Patients
LDL
HDL

Lipoprotein Metabolism in Patients
with Increased LDL and Decreased HDL
Intestine
Liver
LDLr
B-100
E Triglycerides
C-III
VLDL
VLDL
αHDL
CETP
LDL
Modification
Arterial Wall
Macrophage

Clinical Practice
Characteristic Dyslipoproteinemia
in Patients With Residual
In Statin Treated
Patients HDL
Remains an
Independent Risk
Factor
Cardiovascular Risk

LOW HDL-C AS A RESIDUAL RISK FACTOR
FOR CARDIOVASCULAR EVENTS IN TNT
Secondary Prevention TRIAL - Stable Cardiovascular Disease
Major Cardiovascular Event
Frequency (%)
14
12
10
8
6
4
2
0
54
HDL-C quintile (mg/dL)
>100
70-100

Clinical Practice
Characteristic Dyslipoproteinemia
in Patients With Residual
Cardiovascular Risk
In Statin Treated
Patients HDL
Remains an
Independent Risk
Factor
Increased Tg +
Dense LDL +
Decreased HDL
Metabolic Syndrome
Diabetes

THE BEGINNING …

The Super Sized Life Style
WALKING THE DOG

THE RESULT…
OF THE SUPER SIZED LIFE STYLE
Brewer 2010

Visceral Obesity And Cardiovascular
Risk

Current Insights into
the Mechanisms of How
HDL Protects Against
Cardiovascular Disease

Current Insights into the Mechanisms by Which
HDL Protects Against Cardiovascular Disease
Cholesterol
Efflux
HDL

Lipid Poor ApoA-I and αHDL
αHDL is the
Ligand for the
ABCG1 Transporter
Cellular Cholesterol Efflux
“Dual Pathway”
LCAT
αHDL
αHDL
LDL
LCAT
αHDL
A-I
ABCG
1
Preβ-HDL
αHDL
ABCA1
Mediated
Preβ-HDL is the
Ligand for the
ABCA1 Transporter

CURRENT WORKING
MODEL OF HDL AND
CHOLESTEROL
METABOLISM

Intestine
ApoA-I
Current Model of HDL Metabolism
Cholesterol
ApoA-I
ABCA1
A-I
A-I
A-I
A-I
ABCA1
A-I
Liver
A-I
Lipid Poor ApoA-I
SR-B1
LDLr
A-I A-I
CETP
LDL
SR-B1
Modification
ABCG1
ABCA1
LCAT Macrophage
A-I
A-I

Current Insights into the Mechanisms by Which
HDL Protects Against Cardiovascular Disease
Cholesterol
Efflux
HDL
Anti-
Inflammatory
Properties

COLLAR-INDUCED CHANGES IN ENDOTHELIAL
EXPRESSION OF VCAM-1 and ICAM-1 FOLLOWING
EITHER a SALINE OR rHDL Infusion .
Collar-induced Change
3
2
1
0
VCAM-1 ICAM-1
Saline
***
rHDL
Barter P. et al Circ. Res. 2004, 95: 764-772
Saline
**
rHDL
1.5
1.0
0.5
0.0
Collar-induced Change

NEUTROPHIL IMMUNOHISTOCHEMICAL
STAINING In COLLARED CAROTID ARTERY
INFUSED WITH EITHER SALINE OR rHDL
Saline rHDL
Nicholls. S.J. Arter. Throm. Vasc. Biol 2005

Current Insights into the Mechanisms by Which
HDL Protects Against Cardiovascular Disease
Cholesterol
Efflux
HDL
Anti-
Inflammatory
Properties
Protect
LDL From
Oxidation

Major Mechanisms Involved in the HDL
Mediated Protection Against
Cardiovascular Disease
Protect
Oxidation
HDL
LDL Against Oxidation
Oxidation
Ox-LDL
�
Ox-HDL
Paraoxonase (PON)
� LCAT
LpPLA2
�

Current Insights into the Mechanisms by Which
HDL Protects Against Cardiovascular Disease
Stem
Cells
Transport
Particle
Cholesterol
Efflux
HDL
Endothelial
Function
Anti-
Inflammatory
Properties
Protect
LDL From
Oxidation

Clinical Assesment
of HDL
Functional vs.
Dysfunctinal HDL

Potential Mechanisms Involved in
the Generation of Dysfunctional HDL
Dysfunctional
Lyso
PC
Dysfunctional HDL
Ox. PL
HDL
Oxidation
sPLA 2
HDL
Glycation in
Diabetes
Myeloperoxidase
Foger B, et al. J Biol Chem. 1999;274(52):36912-36920.
Ansell BL, et al. Curr Opin Lipidol. 2007;18(4):427-434.
Nicolls SJ , et al. Trends Cardiovasc Med. 2005;15(6):212-221.
Shao B, et al. Curr Opin Mol Ther 2006;8(3):198-205.
N0 2
Dysfunctional HDL
Cl
Dysfunctional HDL

Evidence to Support
Increasing HDL will Decrease
Cardiovascular Disease
�
Pre-Clinical: Animal Models That
Increasing HDL Will Decrease
Atherosclerosis.

Increasing HDL By Infusion of HDL,
Overexpression of the ApoA-I or LCAT Genes
Decreases Atherosclerosis
Infuse HDL
Control
HDL Infused
Badimon et al J. Clin
Invest 1990:85,1234-1241
Increase A-I Gene
Plump et al Proc Natl Acad
Sci 1994:91, 9607- 9611.
Increase LCAT Gene
Hoeg et al Proc Natl Acad
Sci 1996 93:11448- 11453

Evidence to Support
Increasing HDL will Decrease
Cardiovascular Disease
�Pre-Clinical:
Animal Models That
Increasing HDL Will Decrease
Atherosclerosis.
�
Clinical and Imaging: Evidence
That Increasing HDL Will Decrease
Clinical Events and Coronary
Atherosclerosis.
1. Niacin

HDL Targeted Therapies:
Niacin
1. Decreases LDL, increases HDL and reduces
triglycerides
2. Anti-inflammatory
3. Decreases plasma FFA
4. Increases homocysteine
5. Increases uric acid
6. Increases blood glucose
7. Binds to DP2 receptor and causes flushing

Clinical Outcome in Coronary Drug Project**
Event Rate (%)
35
30
25
20
15
10
5
0
-14%*
Nonfatal MI/CD
Death
-27%*
Nonfatal
MI
-26%*
Stroke/
TIA
Placebo
Niacin
-47%*
CV
Surgery
JAMA 1975;231:360-381 *P

HATS: Angiographic and Clinical Endpoints
Change in Stenosis, %
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
+3.9
*
-0.4
Placebo Statin + Niacin
*p

Arbiter 3: Changes in CIMT in Patients Treated
With Statins or Statins + Niacin
Average Change in CIMT For All
Drug Periods (mm)
-
-
-
.075
.050
.025
0
.025
.050
.075
N =
61
Statin
Progression
Regression
N = 125
Statin + Niacin
12 Months
Treatment Period
Taylor A. et al Curr. Med. Res. Opin. 2006:22,2243-2250
N = 67
24 Months

�
�
Aim High randomized 3414 patients with established
CVD– 85% men
� 34% Diabetic and 81% Metabolic Syndrome
�
Patients will receive simvastatin +/- Ezetimibe
to target LDL-C to 40-80 or simvastatin
+/- Ezetimibe + niacin
Baseline lipids: LDL- C = 71 mg/dl, HDL-C = 34.9
mg/dl, Tg = 161 mg/dl.
� Trial Terminated May 2011
AIM HIG Investigators. Am Heart J. 2011;161(3):538-543.
35

�
�
THRIVE will involve a total of 25,000 men and
women
� 8,500 participants will be from the UK
� 10,500 participants will be from China
� 6,000 participants will be from Scandinavia
Patients will receive 40 mg simvastatin +/- Ezetimibe
to target LDL-C to 77 mg/dl or 40 mg simvastatin
+/- Ezetimibe + niacin/laropaprant .
� Completion Date 2013
36

Change in IVUS Total Atheroma Volume
15.0 Progression
5.0
Change in Total Atheroma Volume
0.0
10.0
-5.0
- 10.0
- 15.0
in Clinical Trials
ApoA-I Milano
Placebo All Doses
Regression
Asteriod
Reversal
Pravastatin Atorvastatin
Nicholls S et al JAMA 2007;297:499-508; Nissen S et al NEJM 2007;356:499-508

Evidence to Support HDL as a
Therapeutic Target for the Treatment
√
√
√
of High Risk Patients with
Cardiovascular Disease
Epidemiological Evidence That HDL is an
Independent Risk Factor for Cardiovascular Disease
Prevalence of Low HDL as an Important Risk Factor.
√ Clinical and Imaging Evidence That Increasing HDL
√
Identification of Mechanisms by Which HDL
Decreases Atherosclerosis
Evidence in Animal Models That Increasing HDL Will
Decrease Atherosclerosis.
Will Decrease Clinical Events and Coronary
Atherosclerosis.

Future HDL Targeted
Therapies
1. Preβ-HDL Infusion Therapy

Intestine
Preβ-HDL Removes Cholesterol
Liver
SR-
B1
αHDL
ONLY 5% of HDL is In the Preβ-HDL
Form to Remove Cholesterol from
the Cell
Concept Acute HDL Therapy:
Infuse Preβ-HDL to Increase
Cholesterol Removal from Cells
From Lipid Filled Plaques
LDLr
A-I
95%
LCAT
CETP
LDL
A-I
A-I
A-I
Preβ-HDL
ABCA
1
Lipid Filled
Macrophage
in the Heart

Preβ-HDL Infusion Reduced Arterial
Lipid Stain in
the Artery
Lipid Filled
Macrophage
Stain in the
Artery
Lipid Content in Animal Models
Control ApoA-I Milano
Shah PK,et al. Circulation 2001;103:3047-3050
Control Saline
Infusion
ApoA-I Milano
Infusion
Chiesa G, et al. Circ. Res. 2002:90;974-980
41

IVUS Analysis of the Effect of Preβ-HDL Infusions on
Coronary Plaques in ACS Patients
Protocol for Infusions in ACS Patients
Day 0 1 2 3 4 5 6 7 8
Treatment
Treatment Arm
Control Arm
4 to 7 Weekly Infusions
IVUS IVUS
or Control
Plasma Infusion
Brewer

Preβ-HDL Enriched Plasma Obtained
by HDL Selective Delipidation
Plasma Bag 1
Plasma Collected
A-I
αHDL Preβ-HDL
95% 5%
Waksman R, et al . J Am Coll
Card.2010;55:2727‐2735.
Preβ Enriched Plasma Obtained By
Selective HDL Delipidation
A-I
Preβ-HDL
Plasma Bag 2
Preβ Enriched Plasma
A-I
A-I
A-I
A-I A-I
αHDL Preβ-HDL
20% 80%

Plaque Reduction in the Selective HDL
Delipidation Human Clinical Trial and ApoA-I
Milano Trial were Similar
Variable (mean ± SD)
HDL Delipidation
Therapy Trial*
n = 14
Change in Total Atheroma
Volume (mm 3 ) -12.18 ±
Change in Percent Atheroma
Volume - Plaque Burden -1.0% ±
Change in Most Diseased 10
mm Segment Atheroma
Volume (mm 3 )
*Waksman R, et al. J Am Coll Card. 2010;55:2727-2735
-6.24 ±
ApoA-I Milano
Trial
n = 36
36.75 -14.10 ±
4.0% -1.1% ±
17.94 -7.20 ±
39.50
3.2%
12.60
Nissen S,et al. JAMA 2003;290:2292-2300.

The Reduction in Plaque was Greater in the HDL
Selective Delipidation Human Trial Than the Results
Obtained with Atorvastatin in the REVERSAL Trial
Variable (mean ± SD)
Change in Total Atheroma
Volume (mm 3 ) -12.18 ±
Change in Percent
Atheroma Volume -
Burden
Plaque
Change in Most Diseased
10 mm Segment Atheroma
Volume (mm 3 )
+ P

Future HDL Targeted
Therapies
1. Preβ-HDL Infusion Therapy
2. CETP Inhibitors

Intestine
ApoA-I
Lipoprotein Profile with CETP Inhibition
ApoA-I
ABCA1
Liver
Lipid Poor ApoA-I
SR-B1
LDLr
A-I A-I A-I
HDL-ML,VL, (α1) LCAT
CETP
LDL
A-I
HDL-S, (α4) Modification
SR-B1
ABCG1
A-I
HDL-VS,
Preβ-HDL
ABCA1
Macrophage

CETP Inhibitors
CETP
Torcetrapib
http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc;
Qiu et al. Nat Struct Mol Biol. 2007;14:106–112.;
2ttp://www.ama-assn.org/ama1/pub/upload/mm/ 365/torcetrapib.doc; http:// www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.; Barter P,et al. N Engl J Med.
2007;357:2109–2122.
48

10 mg
30 mg
60 mg
Plasma HDLC and LDLC Levels Following
14 days of Treatment with Torcetrapib
120 mg
120 mg bid
60.2 ± 18.6
48.2 ± 5.7
52.5 ± 15.8
48.5 ± 9.2
53.5 ± 10.7
HDL-C
Dose Baseline Treatment
69 ± 18.9
61.3 ± 5.2
83.2 ± 20.7
84.7 ± 21.6
100 ± 18.6
Phase 2
%
Change
16 ± 8
28 ± 13
62 ± 31
73 ± 21
91 ± 42
Clark RW, et al. Arterioscler Thromb Vasc Biol. 2004;24:490
Baseline
103 ± 21
113 ± 31
102 ± 34
119 ± 19
99 ± 23
LDL-C
Treatment
110 ± 18
97 ± 26
90 ± 36
95 ± 44
59 ± 21
%
Change
9 ± 17
-14 ± 16
-11 ± 20
-21 ± 33
-42 ± 9
49

The Torcetrapib/Atorvastatin
Clinical
Atherosclerosis
Imaging Trials
Coronary IVUS
ILLUSTRATE
Carotid IMT
Radiance I
Radiance II
Trial Program
Phase 3
Morbidity &
Mortality Trial
ILLUMINATE
Patients with CHD or
CHD risk equivalents
15,000 patients in 7
countries
Barter P, et al. N Engl J Med 2007;357:2109–2122. 50

ILLUMINATE: Investigation of Lipid
Level Management to Understand its
�
�
�
�
�
�
Impact in
15, 067 patients
Men and women
Aged 45‐75 years
250 sites in 7 countries
CHD or risk equivalent V D L
No HDL‐C level L restrictionL
L
Titrated statin dose D
Primary End Point
Composite of fatal CHD, nonfatal
MI, stroke (fatal and non‐fatal and
unstable angina requiring
hospitalization
Atherosclerotic Events
T Day
December 2, 2006
Torcetrapib 60 mg + titrated
atorvastatin dose
Titrated atorvastatin dose
H D
L
C E T P
Proposed Duration
4.5‐year 4.5 year follow‐up follow up or 1820
clinical events
Report out ~2010‐2011 ~2010 2011
ILLUMINATE Trial Terminated

Analysis of the Off-Target Characteristics
of the CETP Inhibitors
� Clinical evidence of increased BP
� Preclinical evidence of increased aldosterone production*
�
Preclinical evidence of aldosterone synthase (CYP11B2)
mRNA induction*
� Preclinical evidence of RAAS-associated gene induction*
� L-type Ca 2+ channel activation*
1 Barter P, et al. N Engl J Med. 2007;357:2109–2122; 2 Masson D. Curr Opin Invest Drugs. 2009;10:980-987;
3 Stein E, et al. Am J Cardiol. 2009;104:82–91; 4 Forrest MJ, et al. Br J Pharmacol 2008;154:1465–1473;
5 Stroes ES, et al. Br J Pharmacol. 2009;158:1763–1770; 6 Clerc RG, et al. J Hypertens. 2010;28(8):1676-
1686.

CETP Inhibitors
CETP
Torcetrapib Dalcetrapib
Anacetrapib
http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc;
Qiu et al. Nat Struct Mol Biol. 2007;14:106–112.;
2ttp://www.ama-assn.org/ama1/pub/upload/mm/ 365/torcetrapib.doc; http:// www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.; Barter P,et al. N Engl J Med.
2007;357:2109–2122.
F F
F
F
F F
F
F
F
N
o
o
o
F
53

Effect of 600 mg Dalcetrapib Administration
on Plasma HDL
Stein EA, et al. Eur Heart J. 2010;31(4):480‐488.
Stein E et al. Eur Heart J. 2010;31:480-488.
Increase HDL = 32%
Dalcetrapib Placebo
54

The dal-HEART Program:
Dalcetrapib HDL Evaluation, Atherosclerosis,
and Reverse Cholesterol Transport
dal-VESSEL
450 patients with
CHD or CHD risk
equivalent
To evaluate the
effect of
dalcetrapib on
endothelial
function and BP,
measured by
FMD and ABPM
dal-PLAQuE
130 patients with
CHD
To evaluate the
effect
of dalcetrapib
on
inflammation,
plaque
size, and burden,
measured by
PET/CT and MRI
scans
dal-PLAQUE 2
900 patients
with CAD
To evaluate the
effect of
dalcetrapib on
CVD
progression,
assessed by
IVUS
and carotid Bmode
ultrasound
dal- ACUTE
300 patients
with ACS
To evaluate
the safety and
efficacy of
dalcetrapib in
patients
hospitalized for
ACS. Treatment
initiated within
1 week a nd
last for 20
weeks
ACS=acute coronary syndrome; FMD=flow-mediated dilation; ABPM=ambulatory blood pressure monitoring;
CAD=coronary artery disease; IVUS=intravascular ultrasound; PET=positron emission tomography;
CT=computed tomography; MRI=magnetic resonance
Schwartz GG, et al. Amer. Heart J. 2009;158:896-901
55

CETP Inhibitors
CETP
Torcetrapib Dalcetrapib
Anacetrapib
http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc;
Qiu et al. Nat Struct Mol Biol. 2007;14:106–112.;
2ttp://www.ama-assn.org/ama1/pub/upload/mm/ 365/torcetrapib.doc; http:// www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.; Barter P,et al. N Engl J Med.
2007;357:2109–2122.
F F
F
F
F F
F
F
F
N
o
o
o
F
56

LDL (mg/dL)
Define Trial: Effect of Anacetrapib on Plasma HDL and LDL
110
100
90
80
70
60
50
40
30
20
10
0
Decrease LDL = 40%
6 12 18 24 30 46 62 76
Baseline Week
Anacetrapib Placebo
110
100
90
80
70
60
No. at Risk
Anacetrapib 804 771756 716 687 646 604 568 540
Placebo 803 759759 741 743 735 711 691 666
HDL (mg/dL)
50
40
30
20
10
0
Increase HDL = 138%
6 12 18 24 30 46 62 76
Baseline Week
No. at Risk
Anacetrapib 807 776757 718 687 647 607 572 543
Placebo 804 766761 741 744 736 711 691 666
Cannon CP, et al. N Engl J Med. 2010;363(25):2406‐2415. Copyright © 2010 Massachusetts Medical Society.

• 30,000 patients with occlusive arterial disease
in North America, Europe and Asia
• Background LDL-lowering with atorvastatin
• Randomized to anacetrapib 100 mg vs. placebo
• Scheduled follow-up: 4 years
• Primary outcome: Coronary death, myocardial
infarction or coronary revascularization
www.revealtrial.org

FUTURE THERAPY FOR
CARDIOVASCULAR DISEASE
Combination of Statin and HDL Therapy for the Chronic Protection Against
Cardiovascular Disease
Myocardial
Infarction
Ischemic
Stroke
Drouet L. Cerebrovasc Dis. 2002;13 (Suppl 1):1-6.
Transient Ischemic
Attack
Vulnerable
Plaque
Peripheral Arterial
Disease: