LIPOPROTEIN MANAGEMENT IN ACS
Improving Outcomes in Patients with
Complex Lipid Disorders
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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
• Presenting Physician, MD
Category – Disclosures
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, Sanofi-Aventis, 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: 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 and reduce CVD risk
• Explain the rationale for developing novel agents to increase HDL
• Provide an overview of clinical trials evaluating efficacy and safety of
emerging therapies to modulate HDL
CASE REPORT
Acute Coronary Syndrome
• A 54-year-old male presents with chest pressureassociated dyspnea and vomiting.
• His father had an MI at age 49, and a second MI one
month after the first event.
• Paternal grandfather had 4 MIs with the first event
occurring in his late 40s.
Lab Data in the ER
• Height: 5’8” Weight: 197 lb
• BP: 104/70 mmHg
• Lipid Panel:
―
―
―
―
―
―
―
• BMI: 24.3 kg/m2
• HR: 70/min
Total cholesterol: 167 mg/dL
LDL: 95 mg/dL
HDL: 22 mg/dL
Triglycerides: 250 mg/dL
Non-HDL: 145 mg/dL
Fasting blood glucose: 112 mg/dL
Cr: 0.8 mg/dL
Coronary Angiogram
Angiogram
Atherosclerosis Is an Inflammatory Response
to Excess Apo-B Lipoproteins (Mostly LDL)
Adapted from: Libby P. Sci Amer. 2002;286:46-55.
CASE REPORT: PATIENT WITH METABOLIC SYNDROME
CV Risk Factors
•
•
•
•
•
•
Low HDL-C (22 mg/dL)
High TG (250 mg/dL)
High non-HDL (145 mg/dL)
High fasting blood glucose (112 mg/dL)
(+) family history
Framingham Risk Score: 7% (10-yr risk)
Annual CHD Event Rate Based on the
Framingham Risk Score
Braunwald E. J Am Coll Cardiol. 2006;47(8 Suppl):C101-C103.
Wood D et al. Eur Heart J. 1998;19:A12-A19.
Lifetime Risk for CVD Increases With Greater
Risk Factor Burden
Risk Factor Burden at Age 50 (Estimated Risk by Age 95)
Lifetime Risk for CVD, %
80
69
70
60
50
36
40
10
0
50
Women
Men
39
27
30
20
39
46
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.
Attributable Declines in CHD Deaths
Attributable reduction in CHD deaths (%)
Between 1980 and 2000
Net 44%
↑TG,↓HDL
Target
Population
47%
Therapies
Ford ES et al. N Engl J Med. 2007;356:2389-2398.
Lifestyle/RFs
Unexplained
CAD Hospitalization and Temporal Trends
In Lipid Levels from 2000-2006 (Mean)
Sachdeva A et al. Am Heart J. 2009;157:111-117.e2.
Tim Russert
Residual CVD Risk
• April 2008
– Known CAD (preclinical) on a statin
– LDL-C 67 mg/dl, Triglycerides 300 mg/dl,
HDL 32 mg/dl
– Treadmill stress test: achieved target heart rate without angina or
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.
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 Is Particularly High in
Patients with Diabetes Treated with Statins
Meta-analysis of CHD Patients in 14 Statin Trials1
Major Vascular Event Rate2, %
40
30
34.9
Placebo
Treatment3
CVD Risk Higher Than Patients
With No Diabetes on Placebo
29.6
24.8
19.4
20
Residual
Risk
Residual
Risk
10
0
Diabetes
No Diabetes
Diabetes
Diabetes
1. 4.3-year mean follow-up of 18,686
patients with diabetes; n = 71,370 patients with noNo
diabetes
2. Nonfatal MI, CHD death, stroke, or coronary revascularization
3. Event rate per 1 mmol/L (39 mg/dL) reduction in LDL-C
CTT Collaborators. Lancet. 2008;371:117-125.
Circulating Lipoproteins Play a Major Role
in Atherosclerosis
LDL
HDL
ApoB*
ApoAI
ApoB-containing lipoproteins1
ApoAI-containing lipoproteins1
 Non-HDL (atherogenic)
 HDL (antiatherogenic)
–
–
–
–
–
LDL
IDL
VLDL /VLDL remnants
Chylomicron remnants
Lp(a)
– α-HDL
– Pre-β HDL
*ApoB is a component of all lipoprotein particles currently considered atherogenic2
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.
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.
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
26.3
Standard statin therapy
Intensive high-dose statin therapy
22.4
20
13.7
12.0
10
0
n
LDL-C*
mg/dL
1Superko
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
IDEAL3
IDEAL
8888
104
81
10.9
8.7
TNT4
TNT
10,001
101
77
*Mean or median LDL-C after treatment
Lowering LDL-C Alone is Not Sufficient to
Mitigate 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.
Should High-density Lipoprotein Be a Target
of Therapy ?
• Strength of the association compared with LDL
• Clinical trial evidence
• Why lowering LDL alone is not sufficient
Reducing CAD Risk in Patients with Dyslipidemia
Established
LDL-C
Strong Evidence
HDL-C
Triglycerides
Not Established
Ox = oxidized
Lp(a)
Homocysteine
Ox LDL-C
CRP
Small dense LDL
Coagulability
Lipid Monotherapy Expectations
Clinical and Lipid Effects
Drug
Class
CV Event
Reduction (%)
LDL-C
Decrease (%)
HDL-C
Increase (%)
TG Decrease
(%)
LDL Size/
Buoyancy
Statins
25%-35%
(4S,CARE,
LIPID)
++++
+
+
+
Niacin
14%-27%
(Coronary
Drug Project)
++
++++
++++
+++
+
++
++++
+
Fibrates
22%-24%
(VA-HIT)
Residual CVD Risk: Framingham Heart Study
Low HDL-C Predicts CHD Independent of LDL-C
HDL-C is inversely
correlated with CAD
risk
Correlation is
independent of LDL-C
CAD Risk
After 4 Years*
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
Early and Late Mortality Post-DES
Low vs High HDL at Baseline
Wolfram RM et al. Am J Cardiol. 2006;98:711-717.
Normal Values for Plasma HDL-C*
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.
National Health and Nutrition Examination Survey III
Distribution of Low HDL-C Bottom Tertile of Population
16
% of the Population
14

< 40/50 mg/dL
men/women are
the bottom tertile of
population

<20 mg/dL
occurs in 1/200
men & 1/400
women

<10 mg/dL occurs
in ~1/20,000
Men
12
Women
10
8
6
4
2
0
5-9
10-14
15-19
20-24
25-29
HDL-C (mg/dL)
Miller M, Zahn M. Curr Opin Cardiol. 2004;19:380-384.
30-34
35-39
Potential Antiatherogenic Actions of HDL
Vasodilatory
Activity
Antithrombotic
Activity
Anti-infectious
Activity
Reverse
Cholesterol
Transport
Cellular
Cholesterol
Efflux
Anti-inflammatory
Activity
Antiapoptotic
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.
Antioxidative
Activity
Apo A-I
Apo A-II
Residual CVD Risk: TNT Study
HDL-C 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.
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.
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.
Should High-density Lipoprotein Be a
Target of Therapy ?
ATP III and HDL-C
“A specific HDL cholesterol goal level to reach with
HDL raising therapy is not identified”
However, there are more clinical data to justify HDL as
a therapeutic target in 2011 than there were for LDL in
1988.
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
VA-HIT: Gemfibrozil in Men with CAD
Mean Plasma Lipid Changes, Year One
Lipoprotein, mg/dL
250
200
4% decrease
P<0.001
177
170
Placebo
Gemfibrozil
31% decrease
P<0.001
166
P=NS
113
113
150
100
115
6% increase
P<0.001
32
34
50
0
TC
Rubins HM et al. N Eng J Med. 1999;341:410-418.
LDL
HDL
TG
VA-HIT: Gemfibrozil in Men with CAD
Primary Endpoint Results
Nonfatal MI or CHD Death, %
22% Relative Risk Reduction (P = 0.006)
25
20
21.7
17.3
15
10
5
0
Gemfibrozil
Rubins HB et al. N Eng J Med. 1999;341:410-418.
Placebo
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, 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
Coronary Drug Project – Niacin in Patients with CAD
Clinical Outcomes (Total Follow-up, Adjusted for Baseline)
35
30
- 14%*
Placebo
Niacin
*P<0.05
25
†
20
- 27%*
15
5-year rate
- 26%*
- 47%*†
10
5
0
Nonfatal MI/CHD
Death
Nonfatal MI
Coronary Drug Project Research Group. JAMA. 1975;231:360-381.
Stroke/TIA
CV Surgery
AIM-HIGH
• On-treatment lipids
– 3414 men and women with vascular disease and HDL ≤40 [50-F],
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 ↑ 20% / TG ↓ 25%
– Baseline LDL: 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
Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm.
The Role of HDL Proteins in Reverse
Cholesterol Transport
© 2006 American Society for Clinical Investigation.
Bays H, McKenney J, Davidson M. Expert Rev Cardiovasc Ther. 2005;3:789-820.
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.
CETP Inhibitors and Modulators
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, but Increased Cardiovascular
and Non-cardiovascular Morbidity and Mortality
+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 (%)
“Beneficial” Effects on Lipoproteins, but Increased Cardiovascular
and Non-cardiovascular Morbidity and Mortality (cont)
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.
Off-target Pharmacological Effects of Torcetrapib
• In patients receiving torcetrapib in the ILLUMINATE trial there was a
significant:1
– Increase in blood pressure:
–
–
–
–

5.4 mmHg in SBP in the torcetrapib arm

>15 mmHg in SBP at 12 months in 9.4% of the atorvastatin-only group and 19.5% of
the torcetrapib group (P<0.001)
Decrease in serum potassium
Increase in serum bicarbonate
Increase in serum sodium
Increase in serum aldosterone
• The adverse outcomes in the ILLUMINATE trial may have been the
consequence of off-target actions of torcetrapib and 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 the
CETP Inhibitors
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.
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.
Effects of Anacetrapib 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.
Comparison of the Effect of CETP Agents on
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.
Dalcetrapib Phase IIb Trial
HDL-C Increase at Week 12
Change From Baseline (%)
40
35
*P <0.0001 vs placebo
*
*
30
25
20
*
15
10
5
0
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 Phase IIb Trial
Summary Safety Profile
Pravastatin +
placebo
Pravastatin +
dalcetrapib
300 mg
Pravastatin +
dalcetrapib
600 mg
Pravastatin +
dalcetrapib
900 mg
74
76
68
74
39 (53%)
36 (47%)
38 (56%)
40 (54%)
Cardiac AEs
1 (1%)
4 (5%)
3 (4%)
3 (4%)
Vascular AEs
1 (1%)
2 (3%)
0
0
22 (30%)
17 (22%)
15 (22%)
21 (28%)
Withdrawals due to
AEs
2 (3%)
2 (3%)
2 (3%)
3 (4%)
SAEs
1 (1%)
1 (1%)
1 (1%)
1 (1%)
Deaths
0
0
0
0
n
Any AE
Treatment-related AEs
NOTE: Dalcetrapib 600 mg is the dose used in phase III
Stein EA. Am J Cardiol. 2009;104:82-91.
Conclusions
• Residual CV risk remains problematic despite statinmediated LDL reduction
• HDL-C is an independent risk factor for CHD and metaanalyses and multivariate regression support the hypothesis
that raising HDL-C reduces risk for CVD
• A variety of approaches to HDL therapy are being tested
prospectively in randomized trials
• CETP inhibitors are among the most important novel
therapies for serum HDL modulation
LIPOPROTEIN MANAGEMENT IN ACS
Improving Outcomes in Patients with
Complex Lipid Disorders
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