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HDL: Where are we and where are we going?
1. HDL: Where are we and
where are we going?
Annabelle Rodriguez, MD
Johns Hopkins School of Medicine
Division of Endocrinology
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
2. CAD Risk as a Function of LDL-C and
HDL-C in Men (Ages 50 to 70 Years
Old): Framingham Heart Study
Coronary Artery Disease (CAD)
3
Relative Risk
2
25 0.65
1 45 1.16
65 1.68
0 85 2.2
220 160 100 mg/dL
5.69 4.14 2.58 mmol/L
LDL Cholesterol (LDL-C)
Slide Source
Modified from Castelli WP. Can J Cardiol 1988;4:5A10A. Lipids Online Slide Library
www.lipidsonline.org
3. HDL Metabolism
Nascent HDL (lipid-poor apolipoprotein A1 [Apo A1]) is produced
by the liver and intestine
intestine
liver
particle
LPL uptake
TGRL
selective
uptake
apo A1
HDL2
CETP
ABC1 SR-BI
peripheral cells HL, EL
LCAT
HDL3 PLTP
pre- surface
cubilin HDL remnants
kidney
Slide Source
Von Eckardstein A et al. Curr Opin Lipidol 2000;11:627637. Lipids Online Slide Library
www.lipidsonline.org
4. Potential Targets to Modify HDL
Increase apolipoprotein A1 (apo A1) production
Increase anti-inflammatory effect of high-density
lipoprotein (HDL)
Infuse apo A1 phospholipid complexes
PPAR alpha, delta and gamma
LXR agonists
Upregulate ABCA1 or ABCG1
Enhance LCAT activity
Inhibit CETP
Modify Hepatic Holoparticle uptake of HDL (niacin
receptor agonist)
PPAR=peroxisome proliferator-activated receptor; LXR=liver X receptor; ABCA1=ATP-binding
cassette transporter A1; ABCG1=ATP-binding cassette transporter G1; LCAT=lecithin
Slide Source
cholesterol acyltransferase; CETP=cholesteryl ester transfer protein Lipids Online Slide Library
www.lipidsonline.org
5. Pharmacologic Therapy to Promote
Reverse Cholesterol Transport
Bile Feces
A1
A1 CE
FC
CE LCAT
FC FC
CE
SR-BI Nascent Macrophage
HDL
Liver Mature
HDL
CE=cholesterol ester ;FC=free cholesterol; SR-BI=scavenger receptor class-B, type I;
A1=apolipoprotein A1; LCAT=lecithin cholesterol acyltransferase; HDL=high-density
Slide Source
lipoprotein Lipids Online Slide Library
www.lipidsonline.org
6. Normal Apo A1 and Apo A1 Milano Dimer
Lipid Binding In
Vivo Catabolism
35
143 187
99
243
A1
1
25 209 220
66 121 165
A1=apolipoprotein A1
LCAT Activation Receptor A1m=apolipoprotein A1 Milano
Cholesterol Efflux Binding LCAT=lecithin cholesterol acyl-
transferase
243 243
A1m/A1m 173 173
1 ss 1
Slide Source
Franceschini G. Eur J Clin Invest 1996;26:733746. Lipids Online Slide Library
www.lipidsonline.org
7. HDL Metabolism as a Therapeutic
Target: Potential Strategies
Acute (parenteral) therapies
– Apo A1 Milano/phospholipid complexes
– Apo A1 mimetic peptides
– Large unilamellar vesicles (LUVs)
– Delipidated HDL
– Apo A1 isolated from human plasma and
phosphatidylcholine derived from soybean
Slide Source
HDL=high-density lipoprotein; Apo A1=apolipoprotein A1 Lipids Online Slide Library
www.lipidsonline.org
9. ERASE Trial: Primary Endpoint
Percent Change in Atheroma Volume from
Baseline to 6 weeks
Change in Atheroma Volume (%)
1% The primary endpoint
CSL-111 Placebo
of percent change in
0% atheroma volume from
baseline to 6 weeks did
-1% not differ between
treatment groups
-2% −1.6% (−3.4% in the CSL-111
group vs.
-3% p = 0.48 −1.6% in the placebo
−3.4% group, p=0.48)
-4%
Slide Source
Tardif JC et al. JAMA 2007;297:16751682. Lipids Online Slide Library
www.lipidsonline.org
10. Mechanisms Other Than
Reverse Cholesterol Transport by which
HDL May Be Anti-atherogenic
Anti-oxidant effects
Anti-inflammatory effects
Anti-coagulant effects
Improve endothelial function
Slide Source
HDL=high-density lipoprotein Lipids Online Slide Library
www.lipidsonline.org
11. Conversion of Anti-Inflammatory
and Pro-Inflammatory HDL
Myeloperoxidase
HDL=high-density lipoprotein
Nitrotyrosine
Chlortyrosine
Apo A1
Paraoxonase,
other factors
Apo A1 Pro-inflammatory
factors, other
factors
Anti-inflammatory Pro-inflammatory
Modified from Ansell BJ et al. J Am Coll Cardiol 2005;46:1792 Slide Source
1798. Lipids Online Slide Library
www.lipidsonline.org
12. Regulation of Cholesterol Efflux
in the Macrophage by LXR
A1
CE
ABCG1
LXR
Chol
A1
ABCA1
LXR=liver X receptor; CE=cholesterol ester;A1=apolipoprotein A1; ABCA1=ATP-binding
Slide Source
cassette transporter A1; ABCG1=ATP-binding cassette transporter G1 Lipids Online Slide Library
www.lipidsonline.org
13. Pharmacologic Manipulation of
ABCA1 and Macrophage Cholesterol
Efflux
Fibrates, TZDs, dual PPARs,
new agents
PPAR
PPAR
PPAR
A1
FC LXR/RXR
ABCA1
New
agents
?New
ABCA1=ATP-binding cassette transporter
A1; A1=apolipoprotein A1; FC=free
agents
cholesterol; LXR=liver X receptor;
RXR=retinoid X receptor; PPAR=
peroxisome proliferator-activated Slide Source
receptor; TZD=thiazolidinedione Lipids Online Slide Library
www.lipidsonline.org
14. FIELD Study: Primary Endpoint
Nonfatal MI or CHD death at 5 years
5.9%
6% Full study cohort:
5.2% – Fenofibrate (n=4895)
– Placebo (n=4900)
5%
The primary end point of
nonfatal MI or CHD death was
4% not significantly lower in the
fenofibrate group compared
with the placebo group
3%
P = .16 Nonfatal MI and revascularization
were significantly lower in the
2% fenofibrate group compared with
the placebo group
Patients in the placebo group
1% were treated more frequently
with lipid-lowering therapy
0%
Fenofibrate Placebo MI=myocardial infarction
CHD=coronary heart disease
(n=256) (n=288)
Slide Source
Keech A et al. Lancet 2005;366:18491861. Lipids Online Slide Library
www.lipidsonline.org
15. Total CVD in Subgroups
Feno- Favors Favors HR
Interaction Placebo fibrate Fenofibrate Placebo (95% CI) P
HDL-C P % %
15.1
Low (ATPIII) 13.0 0.02 0.3
2.1%
12.3
High 11.8 0.6
0.5%
Triglycerides
15.4
>1.7 mM 13.6 0.07 0.8
2.8%
12.4
<1.7 11.3 0.2
1.1%
Dyslipidemia (low HDL-C + high TG)
16.3
Yes 14.0 0.06 0.6
2.3%
12.6
No 11.6 0.2
1.0%
CVD=cardiovascular disease 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5
Slide Source
Keech A et al. Lancet 2005;366:1849-1861. Lipids Online Slide Library
www.lipidsonline.org
17. CHICAGO: Mean Change in CIMT
0.020 p=0.017
LS Mean Change from Baseline
0.015 Glimepiride
Posterior Wall CIMT (mm)
0.010 0.012 Pioglitazone
0.005
0.000
-0.005
−0.001
-0.010
Baseline CIMT GLM (N=186) PIO (N=175) Treatment group difference,
LS Mean (SE) 0.779 (0.0085) mm 0.771 (0.0085) mm Final Visit
−0.013 (95% CI: −0.024,−0.002)
CIMT=carotid intima-media thickness
Slide Source
Adapted from Mazzone T et al. JAMA 2006;296:25722581. Lipids Online Slide Library
www.lipidsonline.org
18. HDL Cholesterol Changes
8
Glimepiride Pioglitazone
LS Mean Change from Baseline,
6
HDL-C (mg/dL)
12.8%
4
2
−1.1%
*p<0.0001
0
-2
Baseline 24 48 72
No. of Observations Week
Glimepiride 206 203 206 206
Pioglitazone 201 198 201 201
Slide Source
Mazzone T et al. JAMA 2006;296:2572−2581. Lipids Online Slide Library
www.lipidsonline.org
19. HDL Metabolism: Role of CETP
Bile
A1
FC A1 CE
CE FC LCAT
FC FC
CE ABCA1
SR-BI
Macrophage
Liver CETP
LDLR A1=apolipoprotein A1
ABCA1=ATP-binding cassette transporter A1
CE=cholesterol ester
CETP=cholesterol ester transfer protein
CE FC=free cholesterol
B TG LCAT=lecithin cholesterol acyltransferase
LDL=low-density lipoprotein
LDLR=LDL receptor
SR-BI=scavenger receptor class-B, type I
TG=triglyceride
VLDL/LDL VLDL=very low density lipoprotein
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
20. CETP Deficiency is Associated with
Markedly Increased HDL-C Levels
Bile A1
FC FC A1 CE
CE LCAT
CE FC FC
SR-BI ABCA1
Macrophage
Liver
LDLR
X
CETP A1=apolipoprotein A1
ABCA1=ATP-binding cassette transporter A1
CE=cholesterol ester
CETP=cholesterol ester transfer protein
FC=free cholesterol
CE LCAT=lecithin cholesterol acyltransferase
B TG LDL=low-density lipoprotein
LDLR=LDL receptor
SR-BI=scavenger receptor class-B, type I
TG=triglyceride
VLDL/LDL VLDL=very low density lipoprotein
Slide Source
Lipids Online Slide Library
HDL-C=high-density lipoprotein cholesterol www.lipidsonline.org
21. Torcetrapib: Pharmacodynamic
Effect on HDL-C in Phase 1
Phase I Summary of Lipid and Lipoprotein Changes
100 91 70
80 Base HDL-C 73 60
Base HDL-C (mg/dL)
50
60 62
% Change
% HDL-C
40
40 % Apo A1
28 27 27
24 30
16
20 11 12
20
0 10
−3 −2
-20 0
PBO 10 30 60 120 240 (bid)
Daily Dose
Changes are following 2 weeks of treatment; n=6 per active dose group; n=9 placebo (PBO)
Created from Clark RW et al. Arterioscler Thromb Vasc Biol 2004; Slide Source
Lipids Online Slide Library
24:490497. www.lipidsonline.org
22. Torcetrapib (Study A3071007)
Consistent HDL-C Raising by Gender and
Baseline HDL-C
Mean % Change: 58% 55% 45% 42%
Torcetrapib 120 mg qd
140
130 Male Female
120
110
100
HDL-C 90
(mg/dL) 80
70
60
50
40
30
20
Week: 0 8 0 8 0 8 0 8
Baseline HDL-C: Low High Low High
Slide Source
Created from Bamberger MJ et al. Circulation 2005;112:II-179. Lipids Online Slide Library
www.lipidsonline.org
23. ILLUSTRATE Trial: Primary Endpoint
Percent change in atheroma volume from baseline
0.3 p=0.72
Change in Atheroma Volume
The percent
change in
from Baseline (%)
0.19%
0.2 atheroma volume
did not differ
0.12% between
0.1 treatment groups
0
Torcetrapib Placebo
N = 591 N = 597
Slide Source
Nissen SE et al. N Engl J Med 2007;356:13041316. Lipids Online Slide Library
www.lipidsonline.org
25. Coronary Drug Project:
Clinical Outcomes*
35 −14
30 Placebo
25
Event Rate (%)
Niacin
20 −27
15 −26
10 −47
5
0
Nonfatal MI/ Nonfatal MI Stroke/TIA CV Surgery
CHD Death
MI=myocardial infarction; CHD=coronary heart disease; TIA=transient ischemic attack;
CV=cardiovascular
*Total follow-up, adjusted for baseline characteristics, p<0.05, 5-year rate Source
Slide
Coronary Drug Project Research Group. JAMA 1975;231:360381. Lipids Online Slide Library
www.lipidsonline.org
26. ARBITER 3:
Changes in CIMT – Pooled, 12-Month Data
CIMT=carotid intima-media thickness; ERN=extended-release niacin
Placebo + statin phase
0.075
n = 61
Overall CIMT
regression Significant CIMT progression
Aggregate Change in CIMT for
0.05
Initial 12 months ERN + statin
All Drug Periods (mm)
ANOVA p<0.001 n = 125
0.025 Pooled ARBITER 2 and 3
−0.027 0.011
results
−0.041 0.021
0 Net CIMT regression
−0.027 ± 0.011 mm
p<0.001 vs.
-0.025
placebo
24 month ERN + statin effect
-0.05 n = 57
Mean ± SEM Continuous ERN treatment
-0.075 CIMT regression
Placebo First 12 mos. Total 24 mos.
−0.041 ± 0.021 mm
Phase ERN (+ statin) ERN
(+ Statin) Treatment Period (+ statin) p<0.001 vs. placebo
Slide Source
Taylor AJ et al. Curr Med Res Opin 2006;22:22432250. Lipids Online Slide Library
www.lipidsonline.org
27. MK-0524 (laropiprant)
Suppresses Niacin-Induced Increases in Skin
Blood Flow
1.4
9
Laser Doppler Perfusion Imaging
1.2
Laropiprant 30mg + ER niacin 1500 mg
Placebo-Corrected LDPI
1 Laropiprant 100 mg + ER niacin 1500 mg
Measurement (Volt)
Laropiprant 300 mg + ER niacin 1500 mg
0.8 Aspirin 325 mg Pretreatment + ER niacin 1500 mg
ER niacin 1500 mg
0.6
0.4
0.2
0
2 0
0 30 60 90 120 150 180 210 240 270 300 330 360
ER=extended-release Time (minute, post dose)
Slide Source
Lai E et al. Clin Pharmacol Ther 2007;81:849-857. Lipids Online Slide Library
www.lipidsonline.org
28. Summary
LDL-C remains the primary goal of lipid-treatment but novel
therapies that affect reverse cholesterol transport are on
the horizon
Novel strategies to improve reverse cholesterol transport
include infusions of synthetic HDL or phospholipids, nuclear
receptor agonists to enhance LXR gene regulation, apo A1
peptides to enhance the anti-inflammatory aspects of HDL
and DP-1 antagonists in combination with niacin to improve
compliance
Even small increases in HDL-C may confer substantial
benefit
Intervention to raise HDL-C levels should be considered in
high-risk patients
Slide Source
Lipids Online Slide Library
www.lipidsonline.org