Agents to Raise HDL - · PDF fileAgents to Raise HDL Do we have the right Biomarker of HDL...
Transcript of Agents to Raise HDL - · PDF fileAgents to Raise HDL Do we have the right Biomarker of HDL...
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Jacques Genest MD
Cardiovascular Research Laboratories
McGill University Health Center
Agents to Raise HDL
Do we have the right Biomarker of HDL
function?
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The Case for HDL
The clinical equipoise
HDL-C as a biomarker of CAD, CVD
HDL Functions and biomarkers
Where do we go from here?
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Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quantiles HDL-C
JAMA 2009;302:1993-2000
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Figure 3. Hazard Ratios for Coronary Heart Disease Across Fifths of Usual Lipids or
Apolipoproteins
JAMA 2009;302:1993-2000
Copyright restrictions may apply.
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Human Serum Lipoproteins
Blaha MJ et al., J Clin Lipidol 2008;2:267-273
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Yin and Yang of HDL
The epidemiological association between HDL-C and CVD is strong and coherent.
HDL-C still predicts events if LDL-C is low
Animal data is unequivocal: HDL protect against atherosclerosis
Strong biological plausibility for HDL as a therapeutic target
Mendelian Randomization does not support HDL-Cholesterol as a causal risk factor
The Clinical trial data is neutral (and, in some cases, there is harm)
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Boekholdt MS. Circulation. 2013;128:1504-1512
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HDL Modulators
Fibrates. (Fenofibrate: Accord)
Niacin (Aim High, HPS-2 THRIVE)
CETP inh. Torcetrapib; Dalcetrapib
rHDL: CER, CSL-112
Apolipoprotein mimetics
BET modulators (RVX208; 222)
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Fibrates
Gemfibrozil, Bezafibrate
Fenofibrate
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HDL3 HDL2
CETP
EL/HL CE
LCAT
VLDL
LDL
LDLR
SR-BI
ApoA-I
ABCA1
ABCG1
ABCA1
ABCG5/8
ApoA-I
PLTP
Lipid-poor ApoA-I
Nascent HDL
Kidney
Macrophages Intestine
TG
HDL Metabolism
Cholesterol bilary excretion
Bile acid
Fibrates
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Effects of Combination Lipid Therapy on Cardiovascular Events in Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial
Henry C. Ginsberg, MD College of Physicians & Surgeons , Columbia University, New York For The ACCORD Study Group
Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus The ACCORD Study Group Published at www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)
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ACCORD Study www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)
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Niacin
Aim-HIGH
HPS2-THRIVE
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HDL3 HDL2
CETP
EL/HL CE
LCAT
VLDL
LDL
LDLR
SR-BI
ApoA-I
ABCA1
ABCG1
ABCA1
ABCG5/8
ApoA-I
PLTP
Lipid-poor ApoA-I
Nascent HDL
Kidney
Macrophages Intestine
TG
HDL Metabolism
Cholesterol bilary excretion
Bile acid
Niacin
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AIM-HIGH : Results 50
40
30
20
10
0 0 1 2 3 4
P=0.79 by log-rank best
Niacine plus statine
Placebo plus statine
Années
Po
urc
en
tage
cu
mu
lé d
e p
atie
nts
ave
c d
es
résu
ltat
s p
rim
aire
s
No. à risque
Placebo plus statine 1695 1581 1381 910 436
Niacin plus statine 1718 1606 1366 903 428
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Effect of ERN/LRPT on MAJOR VASCULAR EVENTS
0 1 2 3 4
Years of follow-up
0
5
10
15
20
Pati
ents
su
ffer
ing
even
ts (
%)
15.0% 14.5%
Placebo ERN/LRPT
Logrank P=0.29
Risk ratio 0.96 (95% CI 0.90 – 1.03)
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Effect of ERN/LRPT on SERIOUS adverse events
0 2 4 6 8 10 12
Skin
Bleeding
Heart failure
Musculoskeletal
Gastrointestinal
Infection
New onset diabetes
Diabetic complication
Active
Placebo
Percentage of patients
Excess p value
3.7% <0.0001
1.8% <0.0001
1.4% <0.0001
1.0% <0.0001
0.7% 0.0008
0.4% 0.05
0.7% 0.0002
0.3% 0.0026
ERN/LRPT
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CEPTinh
Torcetrapib; Dalcetrapib
Anacetrapib, Evacetrapib
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HDL3 HDL2
CETP
EL/HL CE
LCAT
VLDL
LDL
LDLR
SR-BI
ApoA-I
ABCA1
ABCG1
ABCA1
ABCG5/8
ApoA-I
PLTP
Lipid-poor ApoA-I
Nascent HDL
Kidney
Macrophages Intestine
TG
CETP inh.
HDL Metabolism
Cholesterol bilary excretion
Bile acid
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Inhibiting CETP
Anacetrapib (REVEAL TIMI 55)
Evacetrapib (ACCELERATE)
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Anacetrapib: Effects on LDL-C and HDL-C
HDL-C
Study Week
Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76
HD
L-C
(m
g/d
L)
(SE
)
0
20
40
60
80
100
120
Anacetrapib
Placebo
Anacetrapib n = 776 757 718 687 647 607 572 543
Placebo n = 766 761 741 744 736 711 691 666
LDL-C
Study Week
Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76
LD
L-C
(m
g/d
L)
(SE
)
0
20
40
60
80
100
Anacetrapib
Placebo
Anacetrapib n = 804 771 716 687 646 604 568 540
Placebo n = 803 759 741 743 735 711 691 666
-39.8% (p<0.001) +138.1% (p<0.001)
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Increasing Apo AI and HDL
Biogenesis
Reconstituted HDL infusions in man
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HDL3 HDL2
CETP
EL/HL CE
LCAT
VLDL
LDL
LDLR
SR-BI
ApoA-I
ABCA1
ABCG1
ABCA1
ABCG5/8
ApoA-I
PLTP
Lipid-poor ApoA-I
Nascent HDL
Kidney
Macrophages Intestine
TG
HDL Metabolism
Cholesterol bilary excretion
Bile acid
rHDL
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Apo AI Proteoliposomes
POPC:Chol:Apo AI
200:20:2
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ApoA-I
+
SR-BI
Oxysterol
Mitochondria Nucleus Cholesterol pool
Passive
Diffusion
LCAT LCAT
RXR LXR
+ABCA1
+ABCG1
ABCG1 ABCA1
Discoidal HDL
Cholesterol
Efflux
Hafiane A. Cholesterol 2013
Cholesterol Efflux
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Nascent HDL structure and Composition
rHDL: Lipid composition resembles raft domains.
Sorci-Thomas MG JLR 2012
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Physicochemical properties and lipid class composition of HDL particle subpopulations.
Kontush A et al. J. Lipid Res. 2013;54:2950-2963
©2013 by American Society for Biochemistry and Molecular Biology
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Specifically, the content of phosphatidylserine revealed positive correlations with all metrics of HDL functionality, reflecting enrichment of phosphatidylserine in small, dense HDL3.
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ERASE Trial: Primary Endpoint
-3.4%
-1.6%
-4%
-3%
-2%
-1%
0%
1%
Percent Change in Atheroma Volume from Baseline to 6 weeks
• The primary endpoint of
percent change in
atheroma volume from
baseline to 6 weeks did
not differ between
treatment groups (-
3.4% in the CSL-111
group vs. -1.6% in the
placebo group, p=0.48)
Placebo CSL-111
Ch
ange
in a
ther
om
a vo
lum
e (%
)
ACC 2007
p = 0.48
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HDL Mimetics
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Apolipoprotein Mimetics
D-4F, rD-4F
5A, 6F
FAMPS, ELK-2A2K2E
ATI-5261, CS-6253
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►The purpose of this study is to investigate
apolipoprotein-mimetic peptides for their ability to
mimic the functionality of HDL particles
►We therefore investigated compound ATI-5261 in the
process of HDL biogenesis
HDL Mimetic Peptide ATI-5261 Promotes Nascent HDL
Formation and Reverse Cholesterol Transport in vitro
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Creation of α-helix peptide ATI-5261
Major lipid-binding motif
270 238
EVRSKLEEWFAAFREFAEEFLARLKS
aa238-266
ATI-5261
263
260 299
Hydrophobic segment
237 216
Acidic residues
Segrest et al. J. Lipid Res., 33(1992), pp.141–166
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ATI-5261 (squares)
Km= 1.04±0.16 ug/ml (0.37±0.05 uM)
Vmax=14.48±0.29% efflux/6h
Vmax/Km=13.92
CS-6253 (triangles)
Km= 2.27±0.16 ug/ml (0.37±0.18 uM)
Vmax=15.25±0.25% efflux/6h
Vmax/Km= 6.71
ApoA-I (circles)
Km= 4.53±0.67 ug/ml (0.15±0.02 uM)
Vmax=14.85±0.02% efflux/6h
Vmax/Km=3.27
Cholesterol efflux in BHK-ABCA1 cells
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Summary
1
2
3
4
5
6
7
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Increasing Apo AI and HDL
Biogenesis
RVX-208
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RVX-208 (BET Bromodomain inh.)
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RVX-208 Sub-Group Analysis (ACC 2014)
40
Conclusion: In ASSURE potentially more favorable effects of the apoA-I inducer, RVX-208, on coronary disease progression and MACE were observed in patients with higher levels of systemic inflammation.
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Why does this NOT work?
HDL might not be causal in protection against atherosclerosis
HDL-cholesterol is a biomarker of CV health
Need for better biomarkers of HDL function
This does not fit the biology
Most likely
Yes, but which one?
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Cellular Cholesterol Efflux
Anti-oxidant
Anti-inflammatory
Vascular Endothelial function
Anti-thrombotic
The Challenge
Develop Biomarkers of HDL Function
That can be tested in outcome studies, be reproducible and brought to high throughput.
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HDL3 HDL2
CETP
EL/HL CE
LCAT
VLDL
LDL
LDLR
SR-BI
ApoA-I
ABCA1
ABCG1
ABCA1
ABCG5/8
ApoA-I
PLTP
Lipid-poor ApoA-I
Nascent HDL
Kidney
Macrophages Intestine
TG
CETP inh.
HDL Metabolism
Cholesterol bilary excretion
Bile acid
Fibrates
rHDL
Niacin
Apo Mimetics RVX
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The Need to Study HDL Function: Potential Novel Therapeutic Approaches.
Dalcetrapib Anacetrapib Evacetrapib
LxR agonists
Apo AI Prod RVX208
PPARα agonists (Fibrates)
LxR agonists FxR agonists BAR agonists PPARα agonists
Niacin
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The HDL pathway remains a sound therapeutic target.
HDL-C is not a good biomarker of therapeutic success
HDL biogenesis, lipidome and proteome may hold the key to novel therapies.
Conclusions