CVD RISK REDUCTION AND LIPID MANAGEMENT
State of the Science in HDL Therapy
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CVD RISK REDUCTION AND LIPID MANAGEMENT
State of the Science in HDL Therapy
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Faculty Disclosures
• The faculty reported the following relevant financial
relationships that they or their spouse/partner have with
TO BE FILLED IN BY
commercial interests:
PRESENTING PHYSICIAN(S)
• Presenter, MD: Research: Pharma Company; Consultant:
Pharma Company
Steering Committee Disclosures
The Steering Committee reported the following relevant financial relationships that they
or their spouse/partner have with commercial interests:
• Robert S. Rosenson, MD, FACC, FACP, FAHA, FNLA: Advisory Board:
Abbott, Amgen, AstraZeneca, LipoScience Inc., Sanofi-Aventis;
Stock Holdings: LipoScience Inc.
• Michael Miller, MD, FACC, FAHA: Consultant: Amarin, Abbott, Roche;
Research: Abbott, Merck, Roche; Speaker: Merck
• Eliot A. Brinton, MD, FAHA, FNLA: Consultant: Abbott, Amarin,
Daiichi-Sankyo, Essentialis, GlaxoSmithKline, Merck, Roche;
Speaker: Abbott, Amarin, Daiichi-Sankyo, GlaxoSmithKline, Merck;
Researcher: Abbott, Amarin, Merck; Scientific Advisory Board:
Atherotech
Non-faculty Disclosures
Non-faculty content contributors and/or reviewers reported the
following relevant financial relationships that they or their
spouse/partner have with commercial interests:
• Barry Watkins, PhD; Bradley Pine; Blair St. Amand;
Jay Katz; Dana Simpler, MD:
Nothing to Disclose
Educational Objectives
At the conclusion of this activity, participants should be able to
demonstrate the ability to:
• Examine the extent of residual CVD risk that continues to burden
dyslipidemic ACS patients despite intensive statin treatment
• Compare the relative effectiveness of existing treatments to raise
HDL and reduce CVD risk
• Explain the rationale for developing CETP modulators and inhibitors
to increase HDL and reduce CVD risk
• Discuss how the modulation of complex cholesterol metabolism could
have an impact on atherogenesis and improve clinical outcomes
Key Learning Messages
• Residual CVD Risk in High-Risk Dyslipidemic Patients
– Lowering LDL-C reduces CVD risk in ACS patients and in general, but
– There is residual CVD risk even with LDL-C controlled on statins
• Relative Prognostic Value of LDL-C and HDL-C for CVD Event Risk
– LDL-C is usually not elevated at time of ACS (average LDL-C ~100 mg/dL)
– HDL-C is usually low at time of ACS (average < 40 mg/dL)
– Low HDL-C is a strong CVD risk factor independent of LDL-C and non-HDL-C
• Growing Appreciation of the Complexities of HDL Metabolism
– HDL particles are heterogeneous in composition and functionality
– Cholesterol efflux by HDL may reflect its antiatherogenic effect
• Rationale for Targeting HDL-C in High-Risk Patients
– The many potential antiatherogenic effects of HDL may be clinically important
– Raising low HDL-C may increase HDL benefits and may be a potential target of therapy
• Current and Emerging Therapeutic Options to Increase HDL Levels
– Niacin increases HDL-C and may reduce CVD risk, but data are inconclusive
– CETP inhibitors increase HDL-C and might reduce CVD risk
Attributable Declines in CHD Deaths
Attributable reduction in CHD deaths (%)
Between 1980 and 2000
Net 44%
↑TG,↓HDL-C
Target
Population
47%
Therapies
Ford ES et al. N Engl J Med. 2007;356:2389-2398.
Lifestyle/RFs
Unexplained
Lowering LDL-C Reduces CVD Risk
in Patients with CAD
High Plasma Apo B Lipoprotein Levels
Promote Atherogenesis
Rationale for therapeutic lowering of Apo B lipoproteins: decrease the
probability of inflammatory response to retention
Apo B lipoprotein
particles
Blood
Monocytes bind to
adhesion molecules
Smooth muscle
Inflammatory
response
Modification
Macrophage
Foam cell
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.
The Apo B-containing (non-HDL)
Lipoprotein Family: All Atherogenic
LDL
ApoB*
ApoB-containing lipoproteins1
– LDL—most common/most important
– IDL
– VLDL /VLDL remnants
– Chylomicron remnants
– Lp(a)
*ApoB is a component of all lipoprotein particles currently considered atherogenic 2
Apo = apolipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein; Lp(a) = lipoprotein (a)
1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3:491-502.
2. Grundy SM. Circulation. 2002;106:2526-2529.
3. Kunitake ST et al. J Lipid Res. 1992;33:1807-1816.
Images available at: http://www.mc.vanderbilt.edu/lens/article/?id=186&pg=999. Accessed January 2010. Adapted with permission.
CHD Events Are Reduced Proportional to LDL-C
Lowering w/ Statins: ACS &Other 2o Prevention Trials
30
y = 0.1629x · 4.6776
R² = 0.9029
P <0.0001
CHD Events (%)
25
4S-P
20
HPS-P
15
HPS-S
A2Z 20
A2Z 80
10
PROVE-IT-AT
5
LIPID-P
4S-S
CARE-P
TNT 10 LIPID-S
IDEAL S20/40
TNT 80
CARE-S
IDEAL A80
PROVE-IT-PR
0
30
50
70
90
110
130
150
LDL Cholesterol (mg/dL)
Updated from O’Keefe J et al. J Am Coll Cardiol. 2004;43:2142-46.
170
190
210
There is Much Residual CVD Risk with
Statins, Even with Intensive Therapy
Residual CVD Risk in Statin vs Placebo Trials
Many CHD Events Still Occur in Statin-Treated Patients
Patients Experiencing
Major CHD Events, %
40
30
20
25-40% CVD Reduction Leaves High Residual Risk
P = 0.003
28.0
19.4
Placebo
Statin
P <0.001
15.9
12.3
10
0
N
 LDL
4S1
4S
4444
-35%
LIPID2
LIPID
9014
-25%
Secondary
Group. Lancet. 1994;344:1383-1389.
Study Group. N Engl J Med. 1998;339:1349-1357.
3Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
P = 0.003
13.2
10.2
CARE3
CARE
4159
-28%
P = 0.0001
11.8
8.7
HPS4
HPS
20
536
-29%
High Risk
14S
4HPS
2LIPID
5Shepherd
P <0.001
7.9
5.5
P <0.001
10.9
6.8
WOSCOPS5 AFCAPS/TexCAPS6
AFCAPS
WOS
6595
6605 /
TexCAPS
-26%
-25%
Primary
Collaborative Group. Lancet. 2002;360:7-22.
J et al. N Engl J Med. 1995;333:1301-1307.
6 Downs JR et al. JAMA. 1998;279:1615-1622.
Residual CVD Risk with Intensive Statin Therapy
Less, but Still Unacceptably High
40
Patients Experiencing
Major CVD Events, %
Statistically significant, but clinically inadequate CVD reduction1
30
26.3
Standard statin therapy
Intensive high-dose statin therapy
22.4
20
13.7
12.0
10
0
n
LDL-C* mg/dL
2
PROVEIT-TIMI
IT-TIMI 22
PROVE
22
4162
95
62
HR. Br J Cardiol. 2006;13:131-136.
CP et al. N Engl J Med. 2004;350:1495-1504.
3Pedersen TR et al. JAMA. 2005;294:2437-2445.
4LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
IDEAL3
IDEAL
8888
104
81
10.9
8.7
TNT4
TNT
10,001
101
77
1Superko
2Cannon
*Mean or median LDL-C after treatment
0.08
High Residual CVD Risk Remains
Even with High-dose Rosuvastatin (JUPITER)
Placebo 251 / 8901
- 44 %
0.04
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Rosuvastatin 20 mg/d 142 / 8901
0.02
Cumulative Incidence
0.06
Primary trial endpoint: MI, Stroke,
UA/ Revascularization, CV Death
0.00
Number Needed to Treat (NNT5) = 25
0
1
2
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
8,901
8,901
8,631
8,621
8,412
8,353
Ridker PM. N Engl J Med. 2008;359:2195-2207.
6,540
6,508
3,893
3,872
1,958
1,963
3
1,353
1,333
4
983
955
544
534
157
174
A Case of Residual CVD Risk on Statin Therapy
• Patient Profile: 57-year-old white male (w/ stressful job)
– Known CAD (preclinical)
– BMI 27 kg/m2
– LDL-C 67 mg/dL
– Triglycerides 300 mg/dL
– HDL-C 32 mg/dL
– Treadmill ECG: achieved target heart rate w/o angina/ischemia
• Medications
– Statin, blood pressure medication, aspirin
• Does this patient require additional treatment? If so, what?
A Case of Residual CVD Risk
• July 2010—clinic visit
– Known CAD (preclinical)
– BMI 27 kg/m2
– Statin compliant
– LDL-C 67 mg/dL; Triglycerides 300 mg/dL; HDL-C 32 mg/dL
– Treadmill ECG: achieved target heart rate w/o angina/ ischemia
• September 2010—sudden death
– AMI and collapse at work
– Attempts to resuscitate fail
• How could this have been avoided?
Annual CHD Event Rate Based on the
Framingham Risk Score
FRAMINGHAM RISK FACTORS
Case
Age: 57 years
Gender: male
Total cholesterol: 150mg/dL
HDL cholesterol: 32 mg/dL
Smoker: no
Systolic BP: 120 mm Hg
On HBP meds: yes
TEN YEAR RISK SCORE: 10%
Braunwald E. J Am Coll Cardiol. 2006;47(8 Suppl):C101-C103.
Wood D et al. Eur Heart J. 1998;19:A12-A19.
CAD Hospitalization and Temporal Trends
In Lipid Levels from 2000-2006 (Mean)
2000
2001
2002
2003
2004
2005
2006
180
172
Lipid Level (mg/dL)
160
140
168
162 162 161
150
120
100
108 108 107 107 105
103 103
80
60
40
43
43
41
41
40
38
38
20
0
LDL → LDL-C
LDL-C
Sachdeva A et al. Am Heart J. 2009;157:111-117.e2.
HDL
→ HDL-C
HDL-C
TGTriglycerides
→ Triglycerides
167
Lifetime Risk for CVD Increases With Greater
Risk Factor Burden
Lifetime Risk for CVD, %
80
Risk Factor Burden at Age 50 (Estimated Risk by Age 95)
69
70
60
46
50
36
40
10
0
39
50
Women
Men
39
27
30
20
50
8
5
All Optimal
≥1 Not Optimal
≥1 Elevated
1 Major
≥2 Major
Lifetime burden stratified for risk factor burden years among Framingham Heart Study participants free of CVD at 50 years.
Optimal risk factors defined as total cholesterol <180 mg/dL, BP <120/<80 mmHg, nonsmoker, and nondiabetic.
Nonoptimal risk factors are defined as total cholesterol 180–199 mg/dL, systolic BP 120–139 mmHg, diastolic BP 80–89 mmHg, nonsmoker, and
nondiabetic. Elevated risk factors are defined as total cholesterol 200–239 mg/dL, systolic BP 140–159 mmHg, diastolic BP 90–99 mmHg,
nonsmoker, and nondiabetic. Major risk factors are defined as total cholesterol ≥240 mg/dL, systolic BP ≥160 mmHg, diastolic BP ≥100 mmHg,
smoker, and diabetic. CVD = cardiovascular disease; BP = blood pressure.
Lloyd-Jones DM et al. Circulation. 2006;113:791-798.
Lifetime Risk of Death from CVD
40
Among Black Men and White Men at 55 Years of Age
≥2 major risk factors
1 major risk factor
≥1 risk factor not optimal
20
all risk factors optimal
0
10
Lifetime Risk (%)
30
≥ 1 elevated risk factor
0
55
60
65
70
75
Attained Age (yr)
Data were derived from 17 studies in a pooled cohort
Berry JD et al. N Engl J Med. 2012;366:321-329.
80
85
90
Lowering LDL-C Alone only Moderately
Reduces CHD Risk
• Statins decrease CVD 25%-45% but leave 55-75% events
not prevented1,2
• Despite on-Rx LDL-C <70-80 mg/dL, many ACS and other
2o prevention patients still have CVD events3,4,5 and these
are related to low HDL-C5
• There is a great need for further improvement in
cardiovascular risk reduction beyond statins6
CHD = coronary heart disease
1. LaRosa J et al. JAMA. 1999;282:2340-2346.
2. HPS Collaborative Group. Lancet. 2002;360:7-22.
3. Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
4. de Lemos JA et al. JAMA. 2004;292:1307-1316.
5. Barter P, et al. New Engl J Med. 2007;357:1301-1310.
6. Assmann G, Gotto AM Jr. Circulation. 2004;109(suppl III):8-14.
Low HDL-C is an Independent
CVD Risk Factor
CHD Risk According to HDL-C Levels
The Framingham Heart Study
CHD risk ratio
4.0
4.0
3.0
2.0
1.0
2.0
1.0
0
25 45 65
HDL-C (mg/dL)
Kannel WB. Am J Cardiol 1983;52:9B-12B.
Copyright ©1983, with permission from Excerpta Medica Inc.
Framingham Heart Study
Low HDL-C Predicts CHD Independent of LDL-C
CAD Risk
After 4 Years*
HDL-C is inversely
correlated with CAD risk
Correlation is
independent of LDL-C
3
2
1
25
45
65
0
85
100
*Men aged 50-70 years
Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a.
160
220
LDL-C, mg/dL
HDL-C
mg/dL
Low HDL-C Predicts Residual CVD Risk After
Optimal Statin Rx: TNT Study
5-Year Risk of Major CVD Events, %
LDL-C ≤70 mg/dL on Statina,b
HDL-C Quintiles,a
mg/dL
Hazard Ratio
Versus Q1*
(Treating to New Targets (TNT) Study)
10
Case: HDL-C 32; LDL-C 67 on statin
8
6
4
2
0
Q1
<38
<37
Q2
Q3
Q4
38
to<42
<43 43
<48 4847to
<55
37 to
42to
to <47
to <55
0.85
level (3 months statin therapy); n = 2661
LDL-C, 58 mg/dL; mean TG, 126 mg/dL
*P=.03 for differences among quintiles of HDL-C
0.57
0.55
Q5
>=55
≥55
0.61
aOn-treatment
bMean
Barter P et al. New Engl J Med. 2007;357:1301-1310.
Early and Late Mortality Post-DES
Low HDL-C vs High HDL-C at Baseline
High HDL-C
Low HDL-C
Wolfram RM et al. Am J Cardiol. 2006;98:711-717.
HDL Consists of Heterogeneous
Particles, but Their Clinical Relevance
Remains to Be Established
Separation of HDL by Physical Properties
• Ultracentrifugation – density
– Isopycnic – preparative
– Density Gradient – Vertical automated profile (VAP)
•
•
•
•
•
Gradient gel electrophoresis (GGE) – size
Rocket immunoelectrophoresis – apolipoprotein content
Nuclear magnetic resonance (NMR) – terminal methyl
2-D gel electrophoresis – size and charge (shape)
Ion mobility – charge (shape) and mass
Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.
Clin Chem. 2011;57(3):392-410.
HDL Subpopulations
Particle Shape
Apolipoprotein Content
Discoidal
Spherical
A-I HDL
A-I/A-II HDL
+other apos: A-IV, C, D, E, etc.
+non-apo proteins: inflam, thromb, etc.
Globular
HDL Particle Size/Electrophoretic Mobility
Lipid-poor apoA-I
HDL2b
HDL2a
HDL3a
HDL3b
--------------------------Alpha-migrating------------------------Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.
HDL3c
Globular
Discoidal
--Pre-beta-migrating--
Potential Antiatherogenic Actions of HDL
HDL inhibits expression of endothelial cell adhesion
molecules and MCP-1
Monocyte
Vessel Lumen
LDL
MCP-1
Adhesion
molecule
Endothelium
LDL
HDL inhibits
oxidation of LDL-C
Cytokines
Oxidized LDL
Intima
Foam
cell
Macrophage
HDL promotes efflux of
cholesterol from foam cells
MCP-1 = monocyte chemoattractant protein-1
Adapted from Barter PJ et al. Circ Res. 2004;95:764-772.
Processes Promoting Efflux of Cholesterol from
Cells to HDL Particles
Extracellular space
Cholesterol deficient,
phospholipid depleted apo A-1
Diffusion
Discoidal HDL
LCAT
SR-B1
Diffusion
Small spherical HDL
LCAT
Larger spherical HDL
ABCA1
SR-B1
ABCG1
Diffusion
SR-B1
ABCG1
Cell membrane
FC
FC
FC
FC
Adapted from Barter P, Rye KA. High density lipoprotein cholesterol: the new target. A handbook for clinicians. 3rd ed.
Birmingham, UK: Sherbourne Gibbs, 2007:31.
Rosen R et al. Circulation. 2012.
Classification of HDL by Physical Properties
Proposed Term
Very Large HDL
(HDL-VL)
Large HDL-V
(HDL-L)
Medium HDL
(HDL-M)
Small HDL
(HDL-S)
Very Small HDL
(VS-HDL)
Density range, g/mL
1.063-1.087
1.088-1.110
1.110-1.129
1.129-1.154
1.154-1.21
Size range, nm
12.9-9.7
9.7-8.8
8.8-8.2
8.2-7.8
7.8-7.2
Density gradient
ultracentrifugation
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c
1.063-1.087
1.088-1.110
1.110-1.129
1.129-1.154
1.154-1.170
Gradient gel
electrophoresis
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c
Size range, nm
12.9-9.7
9.7-8.8
8.8-8.2
8.2-7.8
7.8-7.2
2D gel electrophoresis
Alpha-1
Alpha-2
Alpha-3
Alpha-4
Preβ-1 HDL
Size range, nm
11.2-10.8
9.4-9.0
8.5-7.5
7.5-7.0
6.0-5.0
NMR
Large HDL-P
Size range, nm
12.9-9.7
Ion mobility
HDL2b
HDL2a + 3
Size range, nm
14.5-10.5
10.5-7.65
Density range, g/mL
Medium HDL-P
9.7-8.8
Small HDL-P
8.8-8.2
8.2-7.8
7.8-7.2
Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.
Clin Chem. 2011;57(3):392-410.
Functional and Compositional Assessment of HDL
• Cholesterol efflux
• Antioxidant activity
• Anti-inflammatory activity
• Proteomics/lipidomics
Note: these are research tools w/o known clinical
relevance of application
Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.
Clin Chem. 2011;57(3):392-410.
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 have not yet proven that:
– HDL is a causal factor vs biomarker of risk, or
– Raising HDL-C reduces CVD risk
Should High-density Lipoprotein 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 have increased doubts as to the value of
raising HDL-C
• Recent clinical trial data from next generation investigational
CETP inhibitors has refueled hope that this approach may
increase HDL-C and improve clinical outcomes
Lifestyle Modifications to Raise HDL-C Levels
• Smoking Cessation
− HDL-C levels are 7-20% lower in smokers, but return to normal 1-2 months
after smoking cessation
• Whole Food Plant Based Diet
• Weight Reduction
− For every 3 kg (7 lb) of weight loss, HDL-C levels increase about 1 mg/dL
(~2-4% increase)
• Exercise
− Aerobic exercise (40 min, 3-4 times weekly) increases HDL-C by about
2.5 mg/dL (~5-10% increase)
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.
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.
Reducing CAD Risk in Patients with Dyslipidemia
Established
LDL-C
Reasonable Evidence
HDL-C
Triglycerides
Not Established
Lp(a)
Homocysteine
Oxidized LDL
CRP
Small dense LDL
Coagulability
Available Agents for HDL-C Raising
Agent
Nicotinic acid
Fibrates
Statins
Prescription Om-3*
Bile-acid resins*
Ezetimibe*
Pioglitazone*
Estrogens*
-blockers*
Alcohol*
HDL-C ↑
15-35%
5-20%
5-15%
2-10%
2-5%
1-3%
5-20%
10-25%
10-20%
5-15%
*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.
Primary Use
HDL ↑
TG ↓
LDL ↓
TG ↓
LDL ↓
LDL ↓
Glucose ↓
Hot flashes
BPH
Social, etc.
Risk Reduction for CHD Events
As a Function of Changes in TC, LDL-C, and HDL-C
PERCENT
CHANGE
*4S, CARE, LIPID, WOSCOPS
**HELSINKI, VA-HIT,AFCAPS/TexCAPS
CHD EVENT
RATE
Niacin Increases HDL-C, but May Not
Consistently Reduce CVD Risk
Niacin Reduces CVD Events
Coronary Drug Project
Event Rate (%)
• Subjects: men with prior MI
35
• Treatment arms, 5 lipid meds:
30
– IR Niacin, 1 g TID (n=1119)
estrogen (2 arms),
dextrothyroxine, clofibrate
–14
Placebo
Niacin
25
20
–27
–26
15
– Niacin lipid effects: TC  10%,
TG  27% (HDL-C not meas.) 10
• Results (6 yrs, end-study): benefit
only seen in Niacin arm ( MI 27%,
no  1o endpoint=total mortality)
• Post-study f/u 15 yrs: 4% absolute 
total mortality (NNT = 25)
Coronary Drug Project. JAMA. 1975;231:360-381.
Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255.
–47
5
0
Nonfatal
MI/CHD Death
Nonfatal
MI
Stroke/
TIA
CV
Surgery
Niacin Reduces CVD
Pre-AIM-HIGH Trials
stat sig 27%↓
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: “[A] rigorous test of the HDL hypothesis…”
• 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.
AIM-HIGH—Results
HDL-C at Baseline and Follow-up
Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.
AIM-HIGH—Results
Primary Outcome
1o 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 Early Termination
• Lipids
– Baseline: LDL-C 71 mg/dL w/ prior stain Rx (94% of subjects)
– On Rx: HDL-C ↑ 25% ERN vs ↑ 10% “placebo” (<2/3 of projected)
• Data, Safety and Monitoring Board chose early termination
– Due to futility (likely lack of efficacy) - 1° Endpoint HR 1.05
– Early concern about possible increased stroke rate signal
• Potential explanations for lack of observed efficacy:
– “Placebo” arm received IR niacin, ↑ statin dose & ↑ ezetimibe
(poor test of HDL hypothesis w/ just 15% net ↑ HDL-C)
– Early study termination (VA HIT also negative at 3 y)
– Sl lower than expected event rate (but still >5%/yr)
– High prior statin use (94%, 40%>5y), prior niacin use (20%)
Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm.
Brinton EA. J Clin Lipi. 2011.
Rosenson RS. Curr Athero Rep. 2012 (in press).
CVD Events per Study
AIM-HIGH is Small Relative to Earlier and Later
Niacin Clinical Trials
3515
~4 x ~2300**
~1/7
556*
*At publication 11/15/11. **Estimated. Results due in ~1 year.
Bruckert E et al. Athero. 2010;210:353-361.
Meta-Analysis: Effects of Nicotinic Acid
Major Coronary Events
Treatment
n/N
Control
n/N
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, I2 = 23.0%
Test for overall effect: P < 0.0001
0.75 (0.65, 0.86)
Subtotal excluding CDP
0.53 (0.38, 0.73)
Study
Peto OR
95% Cl
0.1
0.2
0.5
1
Peto OR
95% Cl
2
5
10
Log scale
Many of these trials were tests of drug combinations that included niacin
Bruckert E et al. Atherosclerosis. 2010;210:353-361.
Meta-Analysis: Effects of Nicotinic Acid
Carotid Intima Media Thickness
Study
N
Treatment
Mean (SD)
N
Control
Mean SD
WMD (fixed)
95% Cl
WMD (fixed)
95% Cl
ARBITER-6-HALTS
97
-12 (36)
111
-1 (31)
-12 (-21, -2)
Thoenes M et al
30
-5 (11)
15
9 (12)
-14 (-21, -7)
ARBITER-2
78
14 (104)
71
44 (100)
CLAS
39
-12 (20)
39
12 (20)
-30 (-63, -3)
-25 (-34, -16)
-17 (-22, -12)
Total
Test for heterogeneity: P = 0.13, I2 = 47.4%
Test for overall effect: P < 0.0001
-100
100
E. Bruckert et al, Atherosclerosis 210 (2010) 353-361
-50
0
50
Annual change, μm/y
CETP Inhibitors/Modulators Increase
HDL-C and May Reduce Atherosclerosis
Role of CETP in Atherosclerosis
LDL-R
LDL
VLDL
CE
CETP
Foam
cells
TG
ABC-A1
RCT
Bile
LIVER
HDL
PLASMA
Atherosclerosis
LDL
ABC-G1
Free
cholesterol
PERIPHERAL TISSUE
• Human CETP deficiency
– ↑ in HDL-C (codominant)
– ↓CVD
• Reducing CETP activity →↓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.
Development of CETP Inhibitors/Modulators
CETP Inhibitors and Modulators
Evacetrapib
CETP
Barter et al. N Engl J Med. 2007;357:2109-2122.
Qiu et al. Nat Struct Mol Biol. 2007;14:106-112.
http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc. http://www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.
http://www.ama-assn.org/ama1/pub/upload/mm/365/torcetrapib.doc.
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.
Torcetrapib
“Beneficial” Effects on Lipoproteins
+49%
+55%
+42%
HDL-C
LDL-C
+1% +1%
-1%
Placebo
60 mg
-18%
-20%
90 mg
120 mg
Is the toxicity of torcetrapib related to the mechanism or the molecule?
Barter PJ et al. N Engl J Med. 2007;357:2109-2122.
Torcetrapib: BUT Increased Cardiovascular and
Patients Without Event (%)
Non-cardiovascular Morbidity and Mortality
100
Atorvastatin only
98
HR = 1.25
P = 0.0001
96
94
92
Torcetrapib plus atorvastatin
90
0
0
90 180 270 360 450 540 630 720 810
Days After Randomization
Is the toxicity of torcetrapib related to the mechanism or the molecule?
Barter PJ et al. N Engl J Med. 2007;357:2109-2122.
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 inhibition1,2
1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.
2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.
Analysis of the Off-target Characteristics of
Investigational CETP Inhibitors/Modulators
Characteristic
Torcetrapib Anacetrapib
Dalcetrapib Evacetrapib
Clinical evidence of increased BP
Yes1
No2
No3
No7
Preclinical evidence of increased
aldosterone production*
Yes3
No4
No3
No8
Preclinical evidence of aldosterone
synthase (CYP11B2) mRNA
induction*
Yes3
?
No3
?
Preclinical evidence of RAASassociated gene induction*
Yes5
?
No5
?
L-type Ca2+ channel activation*
Yes6
?
No6
?
1. Barter et al. N Engl J Med. 2007;357:2109-2122.
3. Stein et al. Am J Cardiol. 2009;104:82-91.
5. Stroes et al. Br J Pharmacol. 2009;158:1763-1770.
7. Nicholls et al. JAMA 2011;306:2099-2109
2. Masson D. Curr Opin Invest Drugs. 2009;10:980-987.
4. Forrest et al. Br J Pharmacol. 2008;154:1465-1473.
6. Clerc et al. J Hypertens. 2010: in press.
8. Cao et al. J Lipid Research. 2011;52:2169-2176
Anacetrapib Effects on LDL-C and HDL-C
LDL-C
100
100
-39.8% (P<0.001)
HDL-C (mg/dL) (SE)
LDL-C (mg/dL) (SE)
80
60
40
Anacetrapib
Placebo
20
0
HDL-C
120
Baseline
6
12
18
24
80
+138.1% (P<0.001)
60
40
Anacetrapib
Placebo
20
30
46
62
76
0
Baseline
6
12
18
24
30
46
62
76
Study Week
Study Week
Anacetrapib n = 804 771 716 687 646
604
568
540
Anacetrapib n = 776 757 718 687 647
607
572
543
Placebo n = 803 759 741 743 735
711
691
666
Placebo n = 766 761 741 744 736
711
691
666
Cannon CP et al. N Engl J Med. 2010;363:2406-2415.
Dalcetrapib Phase IIb Trial
HDL-C Increase at Week 12
Change From Baseline (%)
*P <0.0001 vs placebo
*
*
*
placebo
n = 73
dalcetrapib
300 mg
n = 75
NOTE: Dalcetrapib 600 mg is the dose used in phase III
Stein EA. Am J Cardiol. 2009;104:82-91.
dalcetrapib
600 mg
n = 67
dalcetrapib
900 mg
n = 72
Dalcetrapib (JTT-705) Attenuates
Atherosclerosis in Rabbits
Okamoto H et al. Nature. 2000;406:203-207.
Dalcetrapib and Torcetrapib Appear to Differ in
Mechanism of CETP Inhibition
dal
HDL
• Dalcetrapib binds to CETP,
inducing a conformational change
to CETP that hinders association to
HDL1
• Dalcetrapib binds to CETP only2
CETP
tor or ana
HDL
• Torcetrapib binding to CETP is an
irreversible high affinity complex
of CETP inhibitor, HDL, and
CETP2,3
NB: The clinical relevance of these differences is unknown; these
compounds have not been studied in head-to-head clinical trials.
1Okamoto
3Clark
H et al. Nature. 2000;406:203-207.
RW et al. J Lipid Res. 2006;47:537-552.
2Niesor
EJ et al. Atherosclerosis. 2008;199:231.
Termination of Dalcetrapib Clinical Trial
7/7/2012
“The dal-OUTCOMES trial evaluated the efficacy and safety profile of dalcetrapib
when added to existing standard of care in patients with stable coronary heart
disease following an acute coronary syndrome.
Following the results of the second interim analysis of the dalcetrapib
dal-OUTCOMES Phase III trial the Independent Data and Safety Monitoring
Committee (DSMC) has recommended stopping the trial due to a lack of clinically
meaningful efficacy. No safety signals relating to the dal-OUTCOMES trial were
reported from the DSMC.
As a result, Roche has decided to terminate the dal-OUTCOMES trial, as well as
all other on-going studies in the dal-HEART program, including dal-PLAQUE 2 and
dal-OUTCOMES 2. Additional information will be provided in due course as data
become available. ”
Excerpt from letter to dal-OUTCOMES Investigators from Roche.
Conclusions
• Residual CV risk remains problematic despite statin-mediated
LDL-C reduction
• Low HDL-C is an independent risk factor for CHD
• Most clinical trial and observational data suggest that raising
HDL-C may reduce CVD
• HDL particles are very heterogeneous in composition and
function, not all HDL may be anti-atherogenic
• Many new HDL-C raising treatments are in development
• CETP inhibitors greatly raise HDL-C levels, but their effect on
HDL function and clinical outcomes remains in question
Revisiting the HDL Hypothesis
Where to 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
Investigational drugs to raise HDL-C and reduce CVD risk
– CETP inhibitors
– PPAR agonists, APO A1 agonists, delipidating agents, etc.
• But clinical trials have not yet proven that:
– HDL is a causal factor vs biomarker of risk
– Raising HDL-C reduces CVD risk
CVD RISK REDUCTION AND LIPID MANAGEMENT
State of the Science in HDL Therapy
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