LIPOPROTEIN MANAGEMENT IN ACS
Improving Outcomes in Patients with
Complex Lipid Disorders
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LIPOPROTEIN MANAGEMENT IN ACS
Improving Outcomes in Patients with
Complex Lipid Disorders
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please include your email address.
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Thank you.
Faculty Disclosures
The faculty reported the following relevant financial relationships that
they or their spouse/partner have with commercial interests:
TO BE FILLED IN BY
PRESENTING PHYSICIAN(S)
• XXXXXXXXX, MD, FAHA, FNLA
Consultant: Roche, Abbott, Amarin, Daiichi-Sankyo,
GlaxoSmithKline, Merck, Atherotech, Essentialis;
Speaker: Abbott, Daiichi-Sankyo, GlaxoSmithKline,
Merck; Researcher: Abbott, Merck
• XXXXXXXXX, MD, FACC, FAHA
Nothing to disclose
Steering Committee and Consultant Disclosures
The Steering Committee and Curriculum Consultants reported the following relevant
financial relationships that they or their spouse/partner have with commercial interests:
• Michael Davidson, MD: Speakers’ Bureau: Abbott, AstraZeneca, GlaxoSmithKline,
Merck; Advisory Board/Consultant: Abbott, Aegerion, Amgen, AstraZeneca,
Atherotech, Daiichi-Sankyo, DTC MD, Esperion, GlaxoSmithKline, iMD (Intelligent
Medical Decisions), Kinemed, LipoScience, Merck, Novo Nordisk, Roche, SanofiAventis, Synarc, Takeda, Vindico Medical Education; Grant Research: Abbott,
Daiichi-Sankyo, GlaxoSmithKline, Merck, Roche; Board of Directors/Equity: DTC
MD, Omthera, Professional Evaluation Inc., Sonogene
• Peter P. Toth, MD, PhD: Speaker: Abbott, AstraZeneca, Merck, Takeda,
GlaxoSmithKline, Boehringer-Ingelheim; Consultant: Abbott, AstraZeneca, Merck,
Genentech, Genzyme; Advisory Board: Atherotek
• William E. Boden, MD, FACC, FAHA: Speaker: Gilead, Abbott, Sanofi-Aventis,
Kowa
• Michael Miller, MD, FACC, FAHA: Nothing to Disclose
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 need for comprehensive lipid management in
dyslipidemic patients who sustain an ACS
• Compare the relative effectiveness of existing treatments to raise
HDL-C and reduce CVD risk
• Explain the rationale for developing novel agents to increase HDL-C
• Provide an overview of clinical trials evaluating efficacy and safety of
emerging therapies to modulate HDL-C
Key Learning Messages
• Lowering LDL-C reduced CVD risk in patients with CAD
• There is much residual CVD risk even with intense statin therapy
• But half of ACS patients present with LDL-C of 100-120 mg/dL
• Low HDL-C is an independent CVD risk factor
• High HDL-C is antiatherogenic, antiinflammatory, antioxidant, antithrombotic
• Should HDL-C be a target of therapy to reduce CVD risk?
• Niacin and fibrates may increase HDL-C, but do not reduce CVD risk
• CETP inhibitors may increase HDL-C and reduce CVD risk
• Emerging CETP inhibitors are mechanistically diverse
• HDL consists of heterogeneous particles, not all of which are functional
• Functional HDL has high cholesterol efflux capacity
• High cholesterol efflux capacity is associated with antiatherogenic effect
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
Cardiovascular Risk Increases with Increased
Plasma Apo B Lipoproteins
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.
CHD Event Rates in Secondary Prevention
and ACS Statin 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,
Even with Intense Statin Therapy
Reduction in Major Coronary Events in
Major Statin Trials by Level of Patient Risk
Primary
AF/
TexCAPS
6605
-27%
Trial
N
 LDL-C
WOSCOPS
6595
-26%
Secondary
High Risk
ASCOT
10,305
-28%
HPS
20,536
-29%
4S
4444
-36%
LIPID
9014
-25%
CARE
4159
-28%
Risk Reduction, (%)
0
-20
-31*
-40
-38*
-25*
-27‡
-36†
-25§
-38*
Major coronary events defined as: fatal or nonfatal myocardial infarction (MI), unstable angina, sudden cardiac death in
AF/TexCAPS; nonfatal MI or coronary death in WOSCOPS, ASCOT, HPS, LIPID, CARE; coronary death, nonfatal MI, silent
MI, resuscitated cardiac arrest in 4S.
*P<0.001; †P=0.0005; ‡P<0.0001; §P=0.002
LaRosa J et al. JAMA. 1999;282:2340-2346; HPS Collaborative Group. Lancet. 2002;360:7-22; Sever PS et al. Lancet. 2003;361:1149-1158.
Residual CVD Risk in Statin vs Placebo Trials
CHD Events Occur in Patients Treated with Statins
Patients Experiencing
Major CHD Events, %
40
30
20
28.0
Placebo
Statin
19.4
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.
13.2
10.2
CARE3
CARE
4159
-28%
11.8
8.7
HPS4
HPS
20
536
-29%
High Risk
14S
4HPS
2LIPID
5Shepherd
7.9
10.9
5.5
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 in Patients Treated with Intensive
Statin Therapy Remains Unacceptably High
40
Statistically significant, but clinically inadequate CVD reduction1
Patients Experiencing
Major CVD Events, %
30
20
13.7
12.0
10
0
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.
2Cannon
Standard statin therapy
Intensive high-dose statin therapy
22.4
n
LDL-C*
mg/dL
1Superko
26.3
IDEAL3
IDEAL
8888
104
81
10.9
8.7
TNT4
TNT
10,001
101
77
*Mean or median LDL-C after treatment
JUPITER Primary Trial Endpoint
MI, Stroke, UA/Revascularization, CV Death
0.08
Placebo 251 / 8901
0.04
- 44 %
Rosuvastatin 142 / 8901
0.00
0.02
Cumulative Incidence
0.06
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
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
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
• Patient Profile: 58-year-old white male
– Known CAD (preclinical)
– BMI 27
– LDL-C 67 mg/dL
– Triglycerides 300 mg/dL
– HDL-C 32 mg/dL
– Treadmill stress test: achieved target heart rate without angina/ischemia
• Medications
– Statin, blood pressure medication, aspirin
• Does this patient require additional treatment? If so, what?
Grady D. A Search for Answers in Russert’s Death. The New York Times. June 17, 2008.
Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.
Tim Russert: Residual CVD Risk
• April 2008
– Known CAD (preclinical)
– BMI 27
– LDL-C 67 mg/dL; Triglycerides 300 mg/dL; HDL-C 32 mg/dL
– Treadmill stress test: achieved target heart rate without angina/ ischemia
• June 2008
– AMI at work
– Attempts to resuscitate fail
• Could this have been avoided?
Grady D. A Search for Answers in Russert’s Death. The New York Times. June 17, 2008.
Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.
Annual CHD Event Rate Based on the
Framingham Risk Score
FRAMINGHAM RISK FACTORS
Mr. Russert:
Age: 58
Gender: male
Total cholesterol: 150mg/dL
HDL cholesterol: 32 mg/dL
Smoker: no
Systolic BP: 120
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)
Sachdeva A et al. Am Heart J. 2009;157:111-117.e2.
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.
Lowering LDL-C Alone only Moderately
Reduces CHD Risk
• Major statin trials consistently show an approximate 25%-40%
risk reduction for cardiovascular events, regardless of baseline
LDL-C levels1,2
• Despite on-therapy LDL-C <80 mg/dL, a significant number of
ACS patients still have events3,4
• Even with aggressive LDL-C lowering, residual risk remains high
for at least 2 years following an index event, since 2/3-3/4 of
CHD events are not avoided1
• There is a great need for further improvement in cardiovascular
risk reduction5
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. Assmann G, Gotto AM Jr. Circulation. 2004;109(suppl III):8-14.
Low HDL-C is an Independent
CVD Risk Factor
Circulating Lipoproteins Play a Major Role
in Atherosclerosis
LDL
HDL
ApoB*
ApoAI
ApoB-containing lipoproteins1
ApoAI-containing lipoproteins1
 Non-HDL (atherogenic)
– LDL
– IDL
– VLDL /VLDL remnants
– Chylomicron remnants
– Lp(a)
 HDL (antiatherogenic)
– α-HDL
– Pre-β HDL
*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.
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
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.
Early and Late Mortality Post-DES
Low LDL-C versus High HDL-C at Baseline
Wolfram RM et al. Am J Cardiol. 2006;98:711-717.
High HDL-C Levels Reduce CVD Risk
High levels of HDL-C are Anti-atherogenic,
Anti-inflammatory, Anti-oxidant, and
Antithrombotic
Residual CVD Risk: TNT Study
HDL-C Inversely Predictive of Risk Even at LDL-C <70 mg/dL
10
Hazard ratio (95% CI) vs Q1
Q2
0.85 (0.57 - 1.25)
Q3
0.57 (0.36 - 0.88)
Q4
0.55 (0.35 - 0.86)
Q5
0.61 (0.38 - 0.97)
9
8
7
6
5
4
3
2
1
0
Q1
(<37)
Q2
(37 to <42)
Q3
(42 to <47)
Q4
(47 to <55)
Quintile of HDL Cholesterol Level (mg/dl)
Barter P et al. N Engl J Med. 2007;357:1301-1310.
Q5
(≥55)
Each 1 mg/dL
increase in HDL-C
decreases the risk
of major CV
events by
approximately
1.1%, in models
created both at
baseline and at 3
months.
Potential Antiatherogenic Actions of HDL-C
HDL-C inhibits expression of endothelial cell
adhesion molecules and MCP-1
Monocyte
Vessel Lumen
LDL-C
MCP-1
Adhesion
molecule
Cytokines
LDL-C
Endothelium
HDL-C inhibits
oxidation of LDL-C
Oxidized LDL-C
Intima
Foam
cell
Macrophage
HDL-C 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.
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”
However, there are more clinical data to justify HDL-C as
a therapeutic target in 2011 than there were for LDL-C in
1998.
Grundy SM et al. Circulation. 2004;110:227-239.
Effects of Lifestyle Modifications on
HDL-C Levels
• Weight Reduction
− For every 3 kg (7 lb) of weight loss, HDL-C levels increase 1 mg/dL
• Smoking Cessation
− HDL-C levels in smokers are 7%-20% lower than those in
nonsmokers
− HDL-C levels return to normal within 30-60 days after smoking
cessation
• Exercise
− Aerobic exercise (40 min, 3-4 times weekly) increases HDL-C by
about 2.5 mg/dL
Rössner S et al. Atherosclerosis. 1987;64:125-130.
Wood PD et al. N Engl J Med. 1988;319:1173-1179.
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
Strong Evidence
HDL-C
Triglycerides
Not Established
Lp(a)
Homocysteine
Oxidized LDL-C
CRP
Small dense LDL
Coagulability
Effects of Drugs on HDL-C Levels
Nicotinic acid
Fibrates
Estrogens
Statins
α-blockers
Alcohol
↑
↑
↑
↑
↑
↑
15%–35%
10%–15%
10%–15%
5%–10%
10%–20%
10%
Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174.
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 and Fibrates May Increase
HDL-C, but Do Not Consistently
Reduce CVD Risk
FIELD: Fenofibrate in People with DM
Primary Outcome: CHD Events (CHD Death + Nonfatal MI)
Cumulative risk (%)
10
8
Placebo
Fenofibrate
HR = 0.89
95% CI = 0.75–1.05
P=0.16
Although fenofibrate
reduced triglycerides
and LDL-C, there was
virtually no increase
shown in HDL
6
4
2
0
0
1
2
3
4
5
6
2541
2553
837
850
Years from randomisation
FIELD Study 4900
investigators.
Lancet. 2005;366:1849-1861.
Placebo
4835
4741 4646
Fenofibrate 4895 4837 4745 4664
4547
4555
ACCORD Lipid: Results
The combination of fenofibrate and simvastatin failed to reduce the
risk of fatal CV events, nonfatal MI, or nonfatal stroke
Primary and secondary outcomesa
Outcome
Fenofibrate (n=2765), %/y
Placebo (n=2753), %/y Hazard ratio (95% CI)
Primary outcome
2.24
2.41
0.92 (0.79–1.08)
Primary outcome plus revascularization
or hospitalization for CHFb
5.35
5.64
0.94 (0.85–1.05)
Major coronary disease event
2.58
2.79
0.92 (0.79–1.07)
Nonfatal MI
1.32
1.44
0.91 (0.74–1.12)
Any stroke
0.38
0.36
1.05 (0.71–1.56)
Nonfatal stroke
0.35
0.30
1.17 (0.76–1.78)
Death from any cause
1.47
1.61
0.91 (0.75–1.10)
Death from CV causes
0.72
0.83
0.86 (0.66–1.12)
Fatal or nonfatal CHF
0.90
1.09
0.82 (0.65–1.05)
a. At a median of 4.7 years
b. CHF=congestive heart failure
Ginsberg H. Presented at: ACC 2010 Scientific Sessions.
AIM-HIGH
• On-treatment lipids
– 3414 men and women with vascular disease and HDL ≤40,
TG 150-400, LDL-C ≤180 if statin naïve, <160 if on statin
• Therapy
– Simvastatin (40-80 mg) vs simvastatin (40 + niaspan
1500-2000 mg)
• 1° Endpoints
– CHD Death, nonfatal MI, ischemic stroke, high-risk ACS,
hospitalization for coronary or cerebrovascular
revascularization
AIM-HIGH Terminated by Data Safety
Monitoring Board: 36-month Follow-up
• On-treatment Lipids
– HDL-C ↑ 20% / TG ↓ 25%
– Baseline LDL-C: 71 mg/dL
• 1° Endpoints: Negative
– 28 strokes (1.6%) on extended release niacin (ERN)
– 12 strokes (0.7%) in control group
– 9 of 28 strokes in ERN discontinued drug at least 2 months
and up to 4 years before CVA
• Study’s Drug Safety and Monitoring Board recommended
early termination, due to “futility” or lack of efficacy and the
stroke signal
Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm.
CETP Inhibitors Increase HDL-C and
May Reduce Atherosclerosis
Role of CETP Inhibition in Atherosclerosis
LDL-R
LDL
VLDL
CE
CETP
Foam
cells
TG
ABC-A1
RCT
Bile
LIVER
HDL
Atherosclerosis
LDL
ABC-G1
PLASMA
Free
cholesterol
PERIPHERAL TISSUE
• 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.
Emerging CETP Inhibitors are
Mechanistically Diverse
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.
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
Patients Without Event (%)
BUT Increased Cardiovascular and Non-cardiovascular Morbidity
and Mortality
100
Atorvastatin only
98
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.
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
Lipid Effects of CETP Inhibitors/Modulators
% Change from Baseline
CETP Agent
Dose (Mg/day)
HDH-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.
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.
Comparison of the Effect of CETP Agents on
Serum HDL-C·AUC and Fecal Radioactivity
1000
HDL-C•AUC
*P < 0.01
#P < 0.01
*
Fecal [3H] total sterols
*
#
20
15
*
#
10
500
5
0
0
Control
Dalcetrapib
Niesor EJ et al. J Lipid Res. 2010;51:3443-3454.
Torcetrapib
Anacetrapib
Fecal [3H] Total Sterols
(% of Injection)
HDL-C·AUC (mg/dL/day)
1500
Dalcetrapib and Torcetrapib Differ in Mechanism
by Which They Decrease CETP Activity
dal
HDL
• Dalcetrapib binds to CETP,
inducing a conformational change
to CETP that hinders its further
association to HDL1
• Dalcetrapib binds to CETP only2
CETP
tor or ana
HDL
• Torcetrapib or anacetrapib binding
to CETP results in a 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. Therefore, no conclusion should be drawn based on these
comparisons. Clinical development of torcetrapib was halted due to off-target adverse effects.
1Okamoto
H et al. Nature. 2000;406:203-207.
3Clark RW et al. J Lipid Res. 2006;47:537-552.
2Niesor
EJ et al. Atherosclerosis. 2008;199:231.
HDL Consists of Heterogeneous
Particles, but Their Clinical Relevance
Remains to Be Established
HDL Can Be Subdivided into Various Subpopulations
Particle shape
Apolipoprotein composition
Discoidal
Spherical
A-I HDL
A-I/A-II HDL
Particle size
HDL2b
E HDL
Lipid-poor ApoA-I
HDL2a
HDL3a
Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.
HDL3b
HDL3c
Processes Promoting Efflux of Cholesterol from
Cells to HDL Particles
Extracellular space
ABCA1
Lipid-poor ApoA-I
Diffusion
Discoidal HDL
LCAT
Diffusion
Small spherical HDL
LCAT
Larger spherical HDL
SR-B1
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.
Conclusions
• Residual CV risk remains problematic despite statinmediated LDL-C reduction
• Low levels of HDL-C is an independent risk factor for CHD
and meta-analyses and multivariate regression support the
hypothesis that raising HDL-C reduces risk for CVD
• A variety of therapeutic approaches to elevate HDL-C are
being tested prospectively in randomized trials
• HDL-C consists of heterogeneous particles, not all of which
possess functional anti-atherogenic properties
• CETP inhibitors are among the most important novel
therapies for the elevation of functional HDL
LIPOPROTEIN MANAGEMENT IN ACS
Improving Outcomes in Patients with
Complex Lipid Disorders
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