Novel Therapeutic Approaches to Elevate HDL-C and
Modulate HDL Functionality
Daniel J. Rader, MDPerelman School of Medicine
University of Pennsylvania Philadelphia, PA
Novel HDL Therapeutics
• Elevate plasma HDL-C • Enhance cholesterol efflux and
reverse cholesterol transport
Novel HDL Therapeutics
• Elevate plasma HDL-C – CETP inhibition
CETP as a Therapeutic Target
Cholesteryl Ester Transfer Protein
CETP is a 74 kDa plasma protein that circulates in plasma mainly associated with HDL
It is a member of the LPS-binding and lipid transport protein family
It is expressed mainly in liver and adipose tissueCETP exchanges neutral lipids (cholesteryl esters
and triglycerides) among lipoprotein particlesCETP has a net effect of transferring CE out of
HDL in exchange for TGHayek T, et al. JCI 1995;96:20714.Okamoto H, et al. Nature 2000;406:2037.Jiang XC, et al. JBC 1993;268:2740612.
Mechanism of action of CETPTwo hypotheses have been proposed for the mechanism by which CETP transfers neutral lipids between plasma lipoproteins.
(i) a shuttle mechanism that involves CETP collecting cholesteryl esters from one lipoprotein and delivering them through the aqueous phase to another lipoprotein.
(ii) a tunnel mechanism in which CETP bridges two lipoproteins to form a ternary complex, with lipids flowing from the donor to acceptor lipoprotein through the CETP molecule
Barter et al; Biochem J. 1982; 208:1.Ihm et al. J. Lipid Res.1982;23:1328. Swenson et al. J. Biol. Chem. 1988; 263:5150. Tall. J. Lipid Res.1993;34:1255.Zhang et al. Nature Chem Biol. 2012; 8:342.
CETG
CE
HDL TRL
LDL
CETG
CETG
CETG
CETG
CE TG
TG
CETP CETP
CETP
CETP
Barter et al; Biochem J. 1982; 208:1. Swenson et al. J. Biol. Chem. 1988; 263:5150.Tall. J. Lipid Res.1993; 34:1255.
Shuttle Mechanism
CECE
CE
CE
CE
CE
CEHDL
VLDL/LDL
CETP
Binarycomplex
Ternarycomplex
TunnelVLDL/LDL
HDL
Tunnel Mechanism
Ihm et al. J. Lipid Res.1982; 23, 1328. Zhang et al. Nature Chem Biol. 2012; 8:342.
CETP
CECETG
CECE
TG
HDL
Excretion through kidney
TGR-LP
TGCE
CECETG
HDL
Small, dense HDL
Lipid-free/poorapoA-I
HLTG FFA
Role of CETP in the Remodelling of HDL
Rye et al Atherosclerosis, 1999,145:227.Rye et al Arterioscler Thromb Vasc Biol, 2004, 24: 421.
Brown ML, Inazu A, Hesler CB, et al. Nature. Nov 23 1989;342(6248):448-451.Maruyama T, Sakai N, Ishigami M, et al. Atherosclerosis. Jan 2003;166(1):177-185.Nagano M, Yamashita S, Hirano K, et al. J Lipid Res. Jul 2002;43(7):1011-1018.Ritsch A, et al. Arterioscler Thromb Vasc Biol. Dec 1997;17(12):3433-3441.Teh EM, Dolphin PJ, Breckenridge WC, Tan MH. J Lipid Res. Feb 1998;39(2):442-456.
Evidence that Activity of CETP Impacts on Plasma Lipoprotein ConcentrationsThe first genetic deficiency of CETP was identified in Japan in 1989 in patients with markedly elevated HDL-C
57% of Japanese subjects with levels of HDL-C > 100 mg/dL have mutations of the CETP gene
37% of Japanese subjects with levels of HDL-C between 75-100 mg/dL have mutations of the CETP gene
CETP mutations have also been identified outside Japan in association with elevated HDL
Common variants at the CETP locus are strongly associated with variation in HDL-C levels
Relationship of CETP and Atherosclerosis
CETP and Atherosclerosis Human epidemiology
Honolulu Heart Study 7-year prospective dataThere was no statistically significant relation between heterozygous mutations of CETP and CHD or strokeHowever, it was concluded that a deficiency of CETP is athero-protective, so long as it is accompanied by an HDL-C level > 60 mg/dL
Moriyama et al. Prev Med. 1998;27:659–667.
• A meta-analysis has been conducted of studies investigating relationships between CETP polymorphisms and cardiovascular disease in humans
• 46 studies had data on 27,196 coronary cases and 55,338 controls.
• Those polymorphisms that were associated with lower CETP mass and lower CETP activity had higher levels of HDL-C and a significantly reduced coronary risk.
CETP Polymorphisms and Cardiovascular Risk in Humans
Thompson et al JAMA2008;299:2777-2788.
A prospective cohort of 18,245 initially healthy American women
Polymorphisms near or in the CETP gene were associated with both HDL cholesterol concentration and risk of myocardial infarction
It was concluded that decreased CETP activity is associated with an increased level of HDL-C and a decreased risk of myocardial infarction.
CETP Genotypes and CHD in Humans
Ridker et al. Circ Cardiovasc Genet 2009; 2: 26.
CETP and Atherosclerosis in Rodents
Rodents naturally deficient in CETP
Rodents naturally resistant to development of atherosclerosis
Expression of CETP in transgenic mice and rats increases atherosclerosis in most (but not all) models
Marotti et al. Nature.1993;364:73. Plump et al. ATVB.1999;19:1105.
Rabbits have high level of activity of CETP
Rabbits naturally highly susceptible to the development of atherosclerosis
Inhibition of CETP in rabbits decreases atherosclerosis in all models, including genetic manipulation to inhibit CETP, use of an anti-CETP vaccine or by administration of small molecule CETP inhibitors (including dalcetrapib and torcetrapib)
CETP and Atherosclerosis in Rabbits
Sugano et al. J Biol Chem.1998;273:5033. Rittershaus et al. ATVB. 2000;20:2106.Okamoto et al. Nature. 2000;406:203. Morehouse et al. J Lipid Res. 2007;48:1263.
CETP inhibition in Humans
HDL
VLDL/LDL
CE
Liver
Bile
CE
SR-B1
LDL-R
CE
FC
FC
SR-B1
LCATExtrahepatic Tissues
(including the artery wall
Free Cholesterol
CETP
Effect of CETP Inhibition on Plasma Cholesterol Transport
Torcetrapib
CF3
F3C
N O
O
N
OO
CF3
Dalcetrapib
S
O
O
HN
Anacetrapib
O
F3C
O
N
O
F3C
F
CETP Inhibitors
Evacetrapib
Cao et al. J Lipid Res 2011; 52:2169.
Lipid efficacy of CETP inhibitors(% change from baseline)
CETPinhibitor
Dosemg/d
HDL-C%
LDL-C%
TG%
Torcetrapib 60 61 -24 -9
Adapted from Cannon C, JAMA 306:2154; 2011
Torcetrapib
Torcetrapib was an effective CETP inhibitor that was shown in humans to increase the concentration of HDL-C by more than 60% while reducing the concentration of LDL-C by more than 20% over and above the changes achieved by using high doses of statins.
Torcetrapib was the first CETP inhibitor to be tested in human imaging trials and in a large cardiovascular clinical end point trial
Barter et al, NEJM 2007;357:2109.
Coronary IVUS Trial - ILLUSTRATE
• 910 patients with angiographic coronary artery disease treated with torcetrapib 60 mg or placebo in addition to background atorvastatin for 24 months
• Change in coronary atheroma burden was determined in matched arterial segments by intravascular ultrasound
• Relationship between changes in biochemical parameters and plaque burden with treatment was determined
Nissen et al. NEJM. 2007;356:1304. Nicholls et al. Circulation 2008;118:2506.
ILLUSTRATE: Primary Efficacy Parameter
Change in Percent Atheroma Volume
0.19
0.12
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Changein percentatheromavolume
Atorvastatinmonotherapy
Torcetrapib-atorvastatin
p = 0.72†
Nissen et al. NEJM. 2007;356:1304.
ILLUSTRATE: Secondary Efficacy ParametersChange in Normalized
Atheroma Volume (mm3)Change in 10 mm Most
Diseased Segment (mm3)
Nissen et al. NEJM. 2007;356:1304.
Atheroma Regression at Highest HDL-C Levels with Torcetrapib in the ILLUSTRATE
trial
-0.75
-0.50
-0.25
0.00
0.25
0.50
0.75
P=0.004 for trend
LS M
ean
Cha
nge
Per
cent
A
ther
oma
Volu
me
Q1 (<56)
Q3 (69.5-86)
Q2 (56-69)
Q4 (>86)
Quartiles of Achieved HDL Cholesterol (mg/dL)
Nicholls et al. Circulation 2008; 118:2506.
ILLUSTRATE Conclusions
• Torcetrapib 60 mg in combination with atorvastatin increased HDL-C by 61% and lowered LDL-C by 20%, compared with atorvastatin monotherapy.
• However, torcetrapib also increased systolic blood pressure by an average of 4.6 mmHg.
• Torcetrapib-atorvastatin did not reduce the progression of coronary atherosclerosis for the primary efficacy parameter, compared with atorvastatin alone.
• More regression was observed with greater torcetrapib-induced elevations of HDL-C
Carotid IMT trials: RADIANCE 1 and 2B-mode ultrasound every 6 months
SCREENING 24-month double-blind treatment
Atorvastatin only run-inTarget: LDL-C to goal
Torcetrapib/atorvastatin
Atorvastatin
RADIANCE 2
RADIANCE 1
Study Name
904HeFH; eligible for statin treatment8 countries (US, CAN, FRA, ITA, NL, FIN, CZ, S.AFR) 752Mixed hyperlipidemia; eligible for
statin treatment
NSubject PopulationClinical Sites
Dose titration (mg): 10 20 40 80
Kastelein et al. NEJM, 2007; 356:16; Bots et al. Lancet. 2007; 370:153.
RADIANCE 1 Lipids
HDL-C (mg/dL)
Weeks of treatment
40
50
60
70
80
T/AA
110
120
130
140
Weeks of treatment
LDL-C (mg/dL)
0 24 48 72 96 0 24 48 72 96
T/AA
T/A: torcetrapib plus atorvastatin A: atorvastatin alone
Kastelein et al. NEJM, 2007; 356:16.
RADIANCE 1 Imaging primary EndpointMaximum Carotid Intima-Media Thickness
(mm)
2418 126 0
Means +/- SD
1.126 1.1321.133 1.1481.134
1.1631.149 1.1621.1501.152
0
0.5
1
1.5
2
Months of Treatment
T/AA
Average Over 12 Carotid Segments Combined
Max
Car
otid
IMT
(mm
)
Kastelein et al. NEJM, 2007; 356:16.
RADIANCE 1Systolic Blood Pressure (mmHg)
242118151296310
119.0116.0
121.7
116.6
100
105
110
115
120
125
130
Months of treatment
T/AAS
ysto
lic B
P (m
mH
g)
Kastelein et al. NEJM, 2007; 356:16.
RADIANCE 1 Conclusions
• In heterozygous FH, T/A, when compared to A alone– Did not result in regression of atherosclerosis
as assessed by a combined measure of carotid arterial wall thickness
– Caused progression of disease in the common carotid segment
• These effects occurred despite a 52% increase in HDL-C and a 21% decrease in LDL-C
Kastelein et al. NEJM, 2007; 356:16 .
RADIANCE 2 Lipids
40
50
60
70
80
Months of treatment
70
80
90
100
110
0 1 6 12 18 24
HDL-C (mg/dL) LDL-C (mg/dL)
Months of treatment 0 1 6 12 18 24
T/AA
T/AA
T/A: torcetrapib plus atorvastatin A: atorvastatin alone
Bots et al. Lancet. 2007; 370:153.
RADIANCE 2 Imaging Primary EndpointMaximum Carotid Intima-Media Thickness
(mm) Average Over 12 Carotid Segments Combined
Means +/- SD
1.3210 1.35921.31501.36341.3260
1.36801.3319 1.34691.30791.3002
0.60
0.80
1.00
1.20
1.40
1.60
1.80
Months of Treatment
T/AA
2418 126 0
Max
Car
otid
IMT
(mm
)
Bots et al. Lancet. 2007; 370:153.
RADIANCE 2 Systolic Blood Pressure
126.2126.8
125.5
127.3 127.7126.9
120.8 120.8 121.2 121.3122.1 122.2
122.9121.2
126.7
123.7
128.7
119.5119.6120.8
115
120
125
130
Months of Treatment
T/AA
Sys
tolic
BP
(mm
Hg)
242118151296310
Bots et al. Lancet. 2007; 370:153.
RADIANCE 2 Conclusions
• In mixed dyslipidemia, torcetrapib plus atorvastatin, when compared to atorvastatin alone did not result in regression of atherosclerosis as measured by carotid arterial wall thickness
• These effects occurred despite a 63% increase in HDL-C and an 18% decrease inLDL-C
Bots et al. Lancet. 2007; 370:153.
ILLUMINATE: Investigation of Lipid Level Management to Understand its Impact in
Atherosclerotic Events
Torcetrapib 60 mg + titrated atorvastatin dose
Titrated atorvastatin dose
15 067 patients
Primary End Point Composite of fatal CHD, nonfatal MI,
stroke (fatal and non-fatal and unstable angina requiring hospitalization
Men and women Aged 45-75 years 250 sites in 7 countries CHD or risk equivalent, any
HDL-C level, statin eligible
Planned 4.5-year follow-up or 1820
events whichever is later
Barter et al, NEJM 2007;357:2109.
48.5 48.2 48.9 49.2 48.9
79.3 80.5 80.5 80.7
128 127 128 130 129
79.9
0
20
40
60
80
100
120
140
Baseline 1 3 6 12
Study Month
Lipi
ds (m
g/dL
)On Trial Lipid Levels By Study Month
Atorvastatin only Group (Post Run-In)
HDL-C
LDL-C
TG
Barter et al, NEJM 2007;357:2109.
48.6
71.8 77.5 80.9 82.979.7
127115 112 112 112
58.358.259.359.7
0
20
40
60
80
100
120
140
Baseline 1
HDL-C
LDL-C
TG
ILLUMINATE: On Trial Lipid LevelsTorcetrapib/ Atorvastatin Group (Post Run-In)
Study Month
Lipi
ds (m
g/dL
)
-9% (-27,+13)*
+72.1% (34.7) †
-24.9% (28.5) †
3 6 12
Barter et al, NEJM 2007;357:2109.
ILLUMINATE: Primary Endpoint: Time to First MCVE*: Kaplan-Meier Plot
*Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina
Barter et al, NEJM 2007;357:2109.
ILLUMINATE: Secondary EndpointTime to Death: Kaplan-Meier Plot
Barter et al, NEJM 2007;357:2109.
Causes of Death
Fatal stroke
44Reason unknown34Trauma/suicide/homicide42Other non-cardiovascular90Infection
2414Cancer4020Any non-cardiovascular32Other vascular death/procedure related MI21Fatal heart failure41Other cardiac death6086Fatal MI - not procedure related2625Sudden cardiac death4935Any cardiovascular death
Torcetrapib/ Atorvastatin (n=93)
Atorvastatin (n=59 )
Barter et al, NEJM 2007;357:2109.
What was the Reason for the Adverse Outcome with Torcetrapib in the
ILLUMINATE Trial?Possible explanations• Inhibiting CETP is pro-atherogenic
• Inhibiting CETP generates dysfunctional HDL
• Torcetrapib had an adverse off-target pharmacology unrelated to CETP
What was the Reason for the Adverse Outcome with Torcetrapib in the
ILLUMINATE Trial?Possible explanations
• Inhibiting CETP is pro-atherogenic
• Inhibiting CETP generates dysfunctional HDL
• Torcetrapib had an adverse off-target pharmacology unrelated to CETP
In patients receiving torcetrapib in the ILLUSTRATE, RADIANCE 1 & 2 and ILLUMINATE studies there was a significant:
• Increase in blood pressure• Decrease in serum potassium• Increase in serum bicarbonate• Increase in serum sodium• Increase in serum aldosterone
Off-target Pharmacological Effects of Torcetrapib
Barter et al, NEJM 2007;357:2109. Nissen et al. NEJM. 2007;356:1304.Kastelein et al. NEJM, 2007; 356:16. Bots et al. Lancet. 2007; 370:153.
ILLUMINATE: On-Trial Blood Pressure By Study Month
Atorvastatin Group
122.9 128.2*
73.7 75.7*
0 1 3 6 9 12Study Month
40
60
80
100
120
140
Blo
od P
ress
ure
(mm
Hg)
123.0 123.9
73.9 73.7
0 1 3 6 9 12
Torcetrapib plusAtorvastatin Group
* p<0.001 vs atorvastatin at month 12
Barter et al, NEJM 2007;357:2109.
Torcetrapib increases blood pressure in rats, a species that does not have CETP.
Analogues of torcetrapib that do not inhibit CETP raise blood pressure to an extent similar to that observed with torcetrapib
Other CETP inhibitors such as dalcetrapib, anacetrapib and evacetrapib do not raise blood pressure
Off-target Pharmacological Effects of Torcetrapib Unrelated to CETP Inhibition
Forrest et al. Br J Pharmacol. 2008;154:1465. Hu et al. Endocrinology 2009;150:2211.Nicholls et al. JAMA. 2011; 306:2099.
Torcetrapib induces synthesis and secretion of both aldosterone and cortisol from human adrenal cells in tissue culture.
Torcetrapib reduces expression of endothelial nitric oxide synthase mRNA and protein, reduces nitric oxide release, increases expression of endothelin-1 and induces endothelial dysfunction animals independent of CETP inhibition
Other CETP inhibitors such as dalcetrapib and anacetrapib do not have these off-target effects
Forrest et al. Br J Pharmacol. 2008;154:1465-1473. Hu et al. Endocrinology 2009;150:2211-2219. Capponi et al. Circulation 2008;118:S:452. Connelly et al. J Cardiovasc Pharmacol 2010; 55:459.Simic et al. Eur Heart J. 2012 [In Press].
Off-target Pharmacological Effects of Torcetrapib Unrelated to CETP Inhibition
There were 6101 patients with type 2 diabetes in the ILLUMINATE trial
Treatment with torcetrapib resulted in a highly significant improvement in diabetic control
Effects on Diabetic Control in ILLUMINATE
Barter et al. Circulation 2011; 124:555.
A
A
AA
7.4
7.6
7.8
8.0
8.2
8.4
Pla
sma
gluc
ose
(mm
ol/L
)
0 1 3 6Months of treatment
Effects of Atorvastatin (A) vs Atorvastatin Plus Torcetrapib (T/A) in Diabetics in ILLUMINATE
(N = 6661)Glucose
T/A
T/AT/A
T/A
(p<0.0001 for all)
(ns)
Barter et al. Circulation 2011; 124:555.
A A
A A
6.8
6.9
7.0
7.1
7.2
7.3
0 1 3 6
Effects of Atorvastatin (A) vs Atorvastatin Plus Torcetrapib (T/A) in Diabetics in ILLUMINATE
(N = 6661)HbA1C
Months of treatment
HbA
1C (%
)
T/A
T/A T/A
T/A
(p<0.0001 for all)
(ns)
Barter et al. Circulation 2011; 124:555.
A A
120
125
130
135
140
145
0 3
Effects of Atorvastatin (A) vs Atorvastatin Plus Torcetrapib (T/A) in Diabetics in ILLUMINATE
(N = 6661)Insulin
Months of treatment
Insu
lin
U/m
l
T/A
T/A
(ns) (p=0.0007)
Barter et al. Circulation 2011; 124:555.
A
A
46
47
48
49
50
51
0 3
Effects of Atorvastatin (A) vs Atorvastatin Plus Torcetrapib (T/A) in Diabetics in ILLUMINATE
(N = 6661)HOMA-IR
Months of treatment
HO
MA
-IR T/A
T/A
(ns)(p<0.0001)
52
Barter et al. Circulation 2011; 124:555.
Lipid efficacy of CETP inhibitors(% change from baseline)
CETPinhibitor
Dosemg/d
HDL-C%
LDL-C%
TG%
Torcetrapib 60 61 -24 -9
Dalcetrapib 600 31 -2 -3
Adapted from Cannon C, JAMA 306:2154; 2011
dal-HEART Program: dalcetrapib HDL Evaluation, Atherosclerosis &
Reverse Cholesterol Transport
Double-blind, randomized, placebo-controlled studies
dal-OUTCOMES
15,872 patients recently
hospitalized for ACS
CV outcomes
Fully recruited
1. Schwartz et al. Am Heart J. 2009;158:896–901.2. Kastelein et al. Curr Med Res Opin. 2011;27:141–150.3. http://clinicaltrials.gov/ct2/show/NCT00655473; Accessed 21st April 2009.4. http://clinicaltrials.gov/ct2/show/NCT01059682; Accessed February 2nd 2010.5. Roche, data on file.
dal-VESSEL
476 patients with CHD or
CHD risk equivalent
endothelial function and
blood pressure
Completed
dal-PLAQUE
130 patients with CHD
inflammation, plaque size and burden, measured by PET/CT and
MRI
Completed
dal-PLAQUE 2
906 patients with CAD
on atherosclerotic
disease progression, assessed by
imaging
Fully recruited
dal-ACUTE
300 patients hospitalized
for ACS <1 week after
ACS
treatment initiated within 1 week of an
ACSFully
recruited
dal-OUTCOMES 2
20,000 patients with stable
CHD, CHD risk equivalents or at elevated risk
for CVD
CV outcomes
FPI (Feb 2012)
Dal-PLAQUE
dal-PLAQUE was the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.
Co-primary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial.
Fayad et al. Lancet, 2011;378:1547.
130 patients (men and women) aged 18–75 years, with CHD or CHD equivalent
dal-PLAQUE Trial
Dalcetrapib 600 mgTherapy to LDL-C <100 mg/dL
Placebo
Co-primary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months
24 Month follow-up
Fayad et al. Lancet, 2011;378:1547.
Dal-PLAQUE- Results
189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients).
There was no evidence of harm in dalcetrapib treated subjects, with a possible beneficial vascular effects as evidenced by a reduction in total vessel enlargement over 24 months.
Dalcetrapib did not increase blood pressure and thefrequency of adverse events was similar between groups.
It was concluded that these results provided comfort with a decision to proceed with a longer and much larger clinical endpoint trial.
Fayad et al. Lancet, 2011;378:1547.
Dal-VESSEL
This trial investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomised placebo-controlled trial
Luscher et al. European Heart J, 2012;33:857.
476 patients with CHD or equivalentHDL-C < 50 mg/dL
dal-VESSEL Trial
Dalcetrapib 600 mgTherapy to LDL-C <100 mg/dL
Placebo
The primary outcome measures were change from baseline of flow-mediated dilatation of the right brachial artery at 12 weeks and the 24-hour ambulatory blood pressure at week 4.
36 week follow-up
Luscher et al. European Heart J, 2012;33:857.
Dal-VESSEL- Results
476 patients were randomised. Change in FMD was not significantly different from placebo after 12 and 36 weeks of treatment with dalcetrapib.
After 4, 24 and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53 and 56% while at weeks 4, 12 and 36 HDL-C increased by 25, 27 and 31%. Dalcetrapib had no effect on LDL-C levels
Ambulatory blood pressure was unaffected by dalcetrapib up to 36 weeks.
Biomarkers of inflammation, oxidative stress and coagulation were unaffected by dalcetrapib up to 36 weeks, although Lp-PLA2 levels increased by 17%.
Luscher et al. European Heart J, 2012;33:857.
Objective of the dal‐OUTCOMES trial
• To compare the effects of dalcetrapib with placebo, added to evidence‐based background therapy, on cardiovascular risk in patients with recent acute coronary syndrome
15,600 patients 4-12 weeks
after an index ACS event
dal-OUTCOMES Trial
Dalcetrapib 600 mgStatin therapy to optimal LDL-C level
Placebo
Primary End PointCHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest
2.5-year follow-up(Likely to report at
ACC in 2013)
Schwartz et al. Am Heart J. 2009;158:896.
Entry criteria
• Age 45 years• Acute coronary syndrome• Evidence‐based management of LDL‐C• No restriction on entry level of HDL‐C• Key exclusions: Triglycerides >400 mg/dl; treatment with niacin, fibrates, or bile acid sequestrants.
Outcome measures• Primary outcome composite (time to first
occurrence):– Coronary heart disease death– Non-fatal MI– Ischemic stroke– Hospitalization for unstable angina (with
objective evidence of acute myocardial ischemia)– Cardiac arrest with resuscitation
• Secondary outcome measures:– All cause mortality– Coronary revascularization
Flow of patients in the trial• 19,005 entered single blind run-in
• 15,871 patients randomized
• Withdrawal of consent or loss to follow-up: dalcetrapib 3.9%, placebo 3.3%
• At the 2nd pre-specified interim analysis, including 1135 (71% of projected) primary endpoint events, the DSMB recommended termination of the trial for futility.
• At termination, median follow-up 31 mo.
Baseline characteristics(all balanced between treatment groups)
Mean age (years) 60
Female 19%Caucasian 88%
Region
Europe or Israel 50%
North America 32%
Cardiovascular risk factors
Hypertension 68%Metabolic syndrome 63%
Diabetes 24%
Current smoker 21%
Cardiac biomarker‐positive qualifying (index) event 87%
Time from index event to randomization (days) 61
Concurrent treatments(all balanced between treatment groups)
PCI or CABG for index event (before randomization) 91%
Statin 97%
Aspirin 97%
Clopidogrel, ticlopidine or prasugrel 89%
Beta blocker 88%
ACE inhibitor or ARB 79%
Baseline lipids (mean)(all balanced between treatment groups)
mg/dl mmol/L
LDL cholesterol 76 1.96
HDL cholesterol 42 1.09
Triglycerides 134 1.51
HDL‐C and LDL‐C by treatment group
Data aremean ± 95% CI
PlaceboDalcetrapib
PlaceboDalcetrapib
HD
L ch
oles
tero
l (m
g/dl
)LD
L ch
oles
tero
l (m
g/dl
)
Primary outcome* by treatment group
* Coronary heart disease death, non‐fatal MI, ischemic stroke, hospitalization for unstable angina, resuscitated cardiac arrest
Hazard ratio 1.04(95% CI 0.93-1.16)
Risk of primary and secondary outcomesEvent Dalcetrapib
(% at 3 years)Placebo
(% at 3 years)Hazard Ratio (95% CI)
P‐valuePrimary composite 9.2 9.1 1.04 (0.93‐1.16)
0.52CHD death 1.6 1.8 0.94 (0.73‐1.21)
0.66
Non‐fatal MI 5.9 6.0 1.02 (0.89‐1.17)0.80
Unstable angina 1.3 1.3 0.91 (0.68‐1.22)0.54
Resuscitatedcardiac arrest
0.2 0.1 1.41 (0.63‐3.18)0.40
Ischemic Stroke 1.4 1.0 1.25 (0.92‐1.70)0.16
All cause mortality 3.1 3.4 0.99 (0.82‐1.19)0.90
Coronary revascularization
9.5 9.6 1.00 (0.87‐1.11)0.97
Systolic blood pressure and hs‐CRP were slightly higher with dalcetrapib than placebo
With dalcetrapib, compared with placebo:
•Mean systolic blood pressure was 0.6 mm Hg higher (P<0.001)•No effect on plasma aldosterone, bicarbonate, or potassium•No difference in number of anti-hypertensive medications
•At 3 months of assigned treatment, median hs-CRP was 0.2 mg/L higher (P<0.001, based on ANOVA after log transformation)
Conclusions• In patients with recent ACS, the CETP inhibitor dalcetrapib raised HDL‐C by ~30% with minimal effect on LDL‐C and had no effect on the risk of major cardiovascular events.
• HDL‐C concentration did not predict risk in this study population.
• Slightly higher systolic blood pressure and C‐reactive protein with dalcetrapib might reflect an adverse effect of inhibiting CETP.
The two most obvious explanations are:
(i) The increase in HDL-C concentration induced by dalcetrapib is not accompanied by an enhancement of the protective functions of HDL or
(ii) that the inverse relationship between HDL-C concentration and cardiovascular risk observed in population studies is an epiphenomenon rather than being reflective of an ability of HDL to protect against cardiovascular disease.
Why did Dalcetrapib fail to Reduce CV Events?
Lipid efficacy of CETP inhibitors(% change from baseline)
CETPinhibitor
Dosemg/d
HDL-C%
LDL-C%
TG%
Torcetrapib 60 61 -24 -9
Dalcetrapib 600 31 -2 -3
Anacetrapib 100 138 -40 -7
Adapted from Cannon C, JAMA 306:2154; 2011
1620 patients with CHD or CHD risk
equivalents
DEFINE TrialDetermining the EFficacy and Tolerability of
CETP INhibition with AnacEtrapib
Anacetrapib 100 mgStatin therapy to achieve LDL-C <100 mg/dL
Placebo
Primary End PointLipid efficacy and the safety
76 week follow-up
Cannon et al. NEJM. 2010; 363:2406.
DEFINE Trial
Study Week
O 24 760
20
40
60
80
100
120
Anacetrapib
Placebo
LDL-C (mg/dL)
Study Week
0 24 760
20
40
60
80
100
Anacetrapib
Placebo
Cannon et al. NEJM. 2010; 363:2406.
HDL-C (mg/dL)
DEFINE TrialApoA-I (mg/ml)
Study Week
O 24 760
40
80
120
160
200
240 Anacetrapib
Placebo
ApoB (mg/ml)
Study Week
0 24 760
20
40
60
80
100
Anacetrapib
Placebo
Cannon et al. NEJM. 2010; 363:2406.
DEFINE Trial
Study Week
O 24 760
20
40
60
80
100
120
Anacetrapib
Placebo
Study Week
0 24 760
30
60
90
120
150
Anacetrapib
Placebo
Non-HDL-C (mg/dL)TG (mg/dL)
Cannon et al. NEJM. 2010; 363:2406.
DEFINE Trial
Study Week
O 24 760
0.5
1.0
1.5
2.0
2.5
3.0
Anacetrapib
Placebo
Study Week
0 24 760
10
20
30
40
50
Anacetrapib
Placebo
CRP (mg/L)Lp(a) (nmol/L)
Cannon et al. NEJM. 2010; 363:2406.
Anacetrapib had no Effect on BP
SBP
DBP
mm
Hg
mm
Hg
Week
AnacetrapibPlacebo
20016012080400
120
80
40
00 6 12 18 24 30 38 46 54 62 70 76
0 6 12 18 24 30 38 46 54 62 70 76
Cannon et al. NEJM. 2010; 363:2406.
Adjudicated CV Events and Death
Anacetrapib N=808n (%)
Placebo N=804n (%)
Hazard ratio (95% CI) P value
Pre-specified adjudicated CV Safety endpoint 16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40
Cardiovascular Death 4 (0.5) 1 (0.1)Non-fatal MI 6 (0.7) 9 (1.1)Unstable Angina 1 (0.1) 6 (0.7)Non-fatal Stroke 5 (0.6) 5 (0.6)
Death from any Cause 11 (1.4) 8 (1.0)Revascularization 8 (1.0) 28 (3.5) 0.29 (0.13, 0.64) 0.001Death or major CV event (Death/MI/UA/S/Revasc)** 27 (3.3) 43 (5.3) 0.62 (0.38, 1.01) 0.048
Cannon et al. NEJM. 2010; 363:2406.
Primary Bayesian analysis revealed that the event distribution in DEFINE indicates a 94% predictive probability of dismissing a torcetrapib type increase in CV Events
DEFINE trial
Cannon et al. NEJM. 2010; 363:2406.
0.5 1.0 1.5
Primary endpoint: MCVE
Revascularization
0.75 1.25CETP-I Better CETP-I worse
DEFINE trial (2010) N = 1,623 (anacetrapib)
ILLUMINATE Trial (2007) N=15,067 (torcetrapib)
Primary endpoint: MCVE
Revascularization
0.25
ILLUMINATE Trial 2007 (torcetrapib)1
DEFINE Trial 2010 (anacetrapib)2
1. Barter et al, NEJM 2007;357:2109.2. Cannon et al. NEJM. 2010; 363:2406.
30,000 patients aged > 50 with with occlusive
arterial disease
REVEAL TrialRandomized Evaluation of the Effects of Anacetrapib
through Lipid-modification
Anacetrapib 100 mgAtovastatin to achieve LDL-C target
Placebo
Primary End PointCoronary death, myocardial infarction or
coronary revascularization
4 year follow-up
www.revealtrial.org
Sites in North America, Europe and Asia
Planned completion in 2017
Lipid efficacy of CETP inhibitors(% change from baseline)
CETPinhibitor
Dosemg/d
HDL-C%
LDL-C%
TG%
Torcetrapib 60 61 -24 -9
Dalcetrapib 600 31 -2 -3
Anacetrapib 100 138 -40 -7
Evacetrapib 500 129 -36 -17
Adapted from Cannon C, JAMA 306:2154; 2011
Study Design
• Subjects with elevated LDL-C or low HDL-C
• Up to 8 week dietary lead-in period and withdrawalof lipid-modifying therapies
• 12 week treatment period
– Evacetrapib (30, 100 or 500 mg) or placebo
– Evacetrapib 100 mg or placebo in combination with statin therapy (simvastatin 40 mg, atorvastatin 20 mg, rosuvastatin 10 mg)
• Co-primary endpoints: Percent change in HDL-C and LDL-C
Nicholls et al. JAMA. 2011; 306:2099.
Percent Change in HDL-C and LDL-C
* P<0.001 compared with placeboNicholls et al. JAMA. 2011;306:2099.
Percent Change in HDL-C: Evacetrapib Plus Statin
* P<0.001 compared with placeboNicholls et al. JAMA. 2011;306:2099.
Percent Change in LDL-C: Evacetrapib Plus Statin
* P<0.001 compared with placeboNicholls et al. JAMA. 2011;306:2099.
Evacetrapib Conclusions• Evacetrapib monotherapy produced a dose-dependent
increase in HDL-C up to 128.8% and decrease in LDL-C up to 35.9%.
• Significant incremental HDL-C and LDL-C changes were observed when evacetrapib 100 mg was administeredin combination with statins.
• Evacetrapib was well tolerated with no evidence of adverse blood pressure or mineralocorticoid effects.
• The impact of evacetrapib on cardiovascular events remains to be determined.
Nicholls et al. JAMA. 2011; 306:2099.
• There is still a compelling case for further testing the hypothesis that inhibiting CETP by will be anti-atherogenic in humans so long as the hypothesis is tested using potent CETP inhibitors that more than double the level of HDL-C and reduce LDL-C by more than 30%.
• This hypothesis is currently being tested in large CV clinical endpoint trials.
Future of CETP Inhibition as a Strategy to Reduce CV Risk
A-I
Liver
CECE
FCLCAT
FC
Bile
SR-BI
A-I
Macrophage
CEB
LDLR
VLDL/LDL
CETP
TG
ABCA1
ABCG1
XCETP inhibitor
CETP Inhibition: Effect on RCT?
Novel HDL Therapeutics
• Elevate plasma HDL-C • Enhance cholesterol efflux and
reverse cholesterol transport
HDLAnti-oxidant
Anti-thrombotic
Anti-inflammatory
Anti-atherogenic HDL functions
NO-promoting
HDLAnti-oxidant
Anti-thrombotic
Anti-inflammatory
Cholesterol efflux and reverse cholesterol transport
Anti-atherogenic HDL functions
NO-promoting
Reverse Cholesterol Transport
A-I
Liver
CECE
FCLCATFC
Bile
SR-BI
A-I
Macrophage
FCABCA1
ABCG1FC
Quantitation of macrophage reverse cholesterol transport in vivo
Plasma 3H-cholesterol,AcLDL
3H-Chol
Bile
Feces
3H-FC
3H-chol
3H-BA
3H-BA
3H-BA 3H-FC
3H-FC
Macrophage
Genetic and pharmacologic interventions
3H‐Cholesterol
MACROPHAGES
HDL % cholesterol efflux
cAMP
Measuring HDL Cholesterol Efflux Capacity
After George Rothblat, et al
A-I
Liver
CECE
FCLCATFC
Bile
SR-BI
A-I
Macrophage
FCABCA1
ABCG1FC
Promoting Cholesterol Efflux and Reverse Cholesterol Transport
• apoA-I infusion
Normal Apo A1 and Apo A1 Milano Dimer
A1m/A1m
A1
1 1
243243
173173ss
1
25
35
66 121 165209 220
243
18714399
Lipid Binding In Vivo Catabolism
LCAT Activation Cholesterol
Efflux
“Receptor”Binding
Franceschini G. Eur J Clin Invest 1996;26:733–746.
A1=apolipoprotein A1A1m=apolipoprotein A1 MilanoLCAT=lecithin cholesterol acyl-
transferase
Can reconstituted HDL remove cholesterol from plaque?
Recombinant apoA-I Milano Produced Regression of Coronary Atherosclerosis
Nissen SE, et al. JAMA. 2003;290(17):2292-2300. Copyright © 2003 American Medical Association.
ETC-216: apoA-Imilano/phospholipids
Reconstituted HDL: The ERASE Trial
Tardif JC et al. JAMA 2007;297:1675–1682.Tardif JC et al. JAMA 2007;297:1675–1682.
Percent Change in Atheroma Volume from Baseline to 6 weeks
Plasma Selective Delipidation: LS-001 Study
Waksman et al. JACC. 2010:55;2727.
Effects of apoA-I vs LDL Interventions on Coronary Atherosclerosis by IVUS
Intensive Statin Treatment Up to 53% reduction LDL-C for 2 years
apoA-I Milanoor r-HDL
for 4-5 weeks
60 70 90 100 120
0
-5.00
-2.50
+2.50
+5.00
REVERSALpravastatin 40 mg540 days
REVERSALatorvastatin 80 mg540 days
ASTEROID rosuvastatin 40 mg720 days
Progression
Med
ian
Ch
ang
e in
% A
ther
om
a V
olu
me
Courtesy of Dr. Jan Johansson
80 11050Mean LDL-C
ERASEJAMA 2007
VSapoA-I milanoJAMA 2003
Nissen SE, et al. JAMA. 2003;290(17):2292-2300.Tardif JC, et al. JAMA. 2007;297(15):1675-1682.Nissen SE, et al. JAMA. 2006;295(13):1556-1565.Nissen SE, et al. JAMA. 2004;291(9):1071-1080.
Delipidated HDL
A-I
Liver
CECE
FCLCATFC
Bile
SR-BI
A-I
Macrophage
FCABCA1
ABCG1FC
Promoting Cholesterol Efflux and Reverse Cholesterol Transport
• apoA-I infusion• apoA-I upregulation
***
Nicholls SJ, et al. J Am Coll Cardiol. 2011;57(9):1111-1119.Copyright © 2011 American College of Cardiology Foundation.
**P < 0.001*P < 0.01
PlaceboRVX-208 50 mgRVX-208 100 mgRVX-208 150 mg
Efficacy of RVX-208 Time Course of Changes in HDL and
Large Particle HDLHDL Cholesterol Large HDL Particles
1086420
-2Med
ian
Perc
ent C
hang
e
*
25201510
50
-5Med
ian
Perc
ent C
hang
e
Regulation of Macrophage Cholesterol Efflux
A1FC LXR/RXR
PPARPPARPPAR
ABCA1
ABCA1=ATP-binding cassette transporter A1; A1=apolipoprotein A1; FC=free cholesterol; LXR=liver X receptor; RXR=retinoid X receptor; PPAR= peroxisome proliferator-activated receptor; TZD=thiazolidinedione
Oxysterols
FC
A-I
Liver
CECE
FCLCATFC
Bile
SR-BI
A-I
Macrophage
FCABCA1
ABCG1FC
Promoting Cholesterol Efflux and Reverse Cholesterol Transport
• apoA-I infusion• apoA-I upregulation• LXR agonism
Targeting LXR
A1FC LXR/RXR
New agents
PPARPPARPPAR
ABCA1
ABCA1=ATP-binding cassette transporter A1; A1=apolipoprotein A1; FC=free cholesterol; LXR=liver X receptor; RXR=retinoid X receptor; PPAR= peroxisome proliferator-activated receptor; TZD=thiazolidinedione
Effect of LXR Agonist on Macrophage to Feces Reverse Cholesterol Transport
Bile
Feces 3H-BA
3H-BA 3H-FC
3H-FC
3H cholesterol,AcLDL
3H-FC3H-BA
3H cholesterol
LXR agonist
Plasma3H cholesterol
LXR=liver X receptor; BA=bile acid; FC=free cholesterol; AcLDL=acetylated low-density lipoprotein
% C
PM In
ject
ed
An LXR Agonist Significantly Increased Macrophage-to-Feces Reverse Cholesterol Transport in vivo
0.0
0.5
1.0
1.5
2.0
2.5
*
Control LXR Agonist
* P < 0.05 vs vehicle-treated group
Adapted from Naik SU, et al. Circulation. 2006;113(1):90-97.
A-I
Liver
CECE
FCLCATFC
Bile
SR-BI
A-I
Macrophage
FCABCA1
ABCG1FC
Promoting Cholesterol Efflux and Reverse Cholesterol Transport
• apoA-I infusion• apoA-I upregulation• LXR agonism• miR-33 antagonism
Targeting miR-33
A1FC LXR/RXR
miR-33
ABCA1Anti-
miR-33
A-I
Liver
CECE
FCLCATFC
Bile
SR-BI
A-I
Macrophage
FCABCA1
ABCG1FC
Promoting Cholesterol Efflux and Reverse Cholesterol Transport
• apoA-I infusion• apoA-I upregulation• LXR agonism• miR-33 antagonism• LCAT infusion/activation
The HDL flux hypothesis
A-I
CECE
FCLCATFC
Bile
SR-BI
A-I
ABCA1
Macrophage
FC
ABCG1
HL, EL
CEB
LDLR
VLDL/LDL
CETP
TG
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