1. Rationale for Targeting HDL
Steven E. Nissen MD
Disclosure
Clinical Trials: AstraZeneca, Eli Lilly, Novartis, Takeda, Resverlogix, Orexigen, Vivus, and Pfizer.
Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor a tax deduction is received.

2. Steven E. Nissen, MD
Clinical Trials: AstraZeneca, Eli Lilly, Novartis, Takeda, Resverlogix, Orexigen, Vivus, and Pfizer.
Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor a tax deduction is received.

3. Acknowledgements
H. Bryan Brewer, Jr, MD MedStar Research Institute Washington, DC
Philip Barter The Heart Research Institute Sydney, Australia
Stephen J. Nicholls South Australian Health and Medical Research Institute Prof. of Cardiology, University of Adelaide, Australia

4. Residual Clinical Risk in Statin Trials

5. HDL as a Therapeutic Target
Surface Monolayer of Phospholipids
and Free Cholesterol
apoA-I
apoA-II
Hydrophobic
Core of Triglyceride
and Cholesteryl Esters
Rye Atherosclerosis 1999

6. Heterogeneity of Circulating HDL Particles
Apolipoprotein Composition
Particle Shape
Discoidal
Spherical
(A-I)HDL
(A-I/A-II)HDL
(A-II)HDL
Particle Size
Lipid-poor/Lipid-free
apoA-I
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c

7. 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)
Potential targets to modify HDL
There are several potential targets to modify reverse cholesterol transport (RCT). Based on animal models and genetic disorders, increases in apo A1 production would most likely result in the most favorable improvement in RCT. Synthetic forms of HDL, HDL mimetics, reconstituted HDL, and reinfusing delipidated HDL are all potential therapeutic approaches in human clinical trials. LXR is the nuclear receptor that protects cells from cholesterol toxicity. Oxysterols are ligands for LXR, and if elevated, they upregulate LXR, resulting in the cellular transduction of the ATP-binding cassette sterol transporters, such as ABCA1 and ABCG1, that efflux free cholesterol into either nascent HDL (ABCA1) or mature HDL (ABCG1). Enhancing LCAT activity will increase the esterification of cholesterol in HDL, resulting in HDL maturation. Inhibiting CETP will increase HDL particle size and delay catabolism of HDL. Modifying the holoparticle uptake of HDL (a possible medication of niacin) will also delay catabolism by allowing the HDL particle to continue circulating and potentially increase RCT. HDL=high-density lipoprotein
LXR=liver X receptor
ABCA1=ATP-binding cassette transporter A1
ABCG1=ATP-binding cassette transporter G1
LCAT=lecithin cholesterol acyltransferase
CETP=cholesteryl ester transfer protein

8. Why should we believe that HDL therapy will improve outcomes?

9. Framingham Heart Study
CAD Risk in Relation to Levels of LDL-C and HDL-C in Men (Ages 50 to 70 Years)
Framingham Heart Study
mmol/L
mg/dL
CAD Relative Risk
CAD risk as a function of LDL-C and HDL-C in men (ages 50 to 70 years old): Framingham Heart Study
The lower the high-density lipoprotein cholesterol (HDL-C) level, the greater is the likelihood of developing coronary artery disease (CAD). This relationship of risk is gradually enhanced as low-density lipoprotein cholesterol (LDL-C) levels are increased. The risk nearly reaches 3-fold when LDL-C is 220mg/dL and HDL-C is 25mg/dL. HDL-C remains an important risk factor even in patients with a low LDL-C level. For example, a patient with an LDL-C of 100mg/dL and an HDL-C of 25mg/dL has a similar risk of coronary heart disease as a patient with an LDL-C of 220mg/dL and an HDL-C of 45mg/dL. Reference:
Castelli WP. Cholesterol and lipids in the risk of coronary artery disease—the Framingham Heart Study. Can J Cardiol .1988;4:5A-10A.
HDL Cholesterol
mg/dL
mmol/L
LDL Cholesterol
Reprinted from Castelli WP. Can J Cardiol. 1988;4:5A–10A,

10. MACE Rates vs. On-treatment HDL-C and LDL-C
Outcomes in the Treating to New Targets (TNT) Trial
Atorvastatin 10 mg
Atorvastatin 80 mg
Mean LDL-C 99 mg/dL
Mean LDL-C 73 mg/dL
Percentage of Patients
Major cardiovascular events according to on-treatment HDL-C: Treating to New Targets (TNT) trial
The Treating to New Targets (TNT) trial demonstrated that atorvastatin 80 mg with an on-treatment low-density lipoprotein cholesterol (LDL-C) of 73 mg/dL decreased coronary events in a coronary heart disease patient population more than atorvastatin 10 mg with an on-treatment LDL-C of 99mg/dL. Low high-density lipoprotein cholesterol (HDL-C) (i.e., HDL-C <40 mg/dL) was associated with a higher residual risk even in patients with a low LDL-C. References:
Barter PJ, Kastelein JJ. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol. 2006;47:
Waters DD, LaRosa JC, Barter P, et al. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol. 2006;48:
On-treatment HDL-C (mg/dL)
Barter PJ, Kastelein JJ. J Am Coll Cardiol. 2006;47:492–499. |
Waters DD, et al. J Am Coll Cardiol. 2006;48:1793–1799.

12. ApoA1 Milano: Change in Atheroma Volume
-2.9 mm3
P = 0.97
-12.6 mm3
-14.1 mm3
-15.1 mm3
P = 0.007
P < 0.001
P = 0.02
Placebo
Low Dose
High Dose
Combined

13. Does the 3-15% increase in HDL make a difference?
Statins and HDL
Does the 3-15% increase in HDL make a difference?

14. Impact of LDL-C Lowering on Plaque Progression
Pooled results from 6 major IVUS outcomes trials 4 5 6 7 8 9 1 - 2 L D C u r i n g T e a t m , / d
Change in
PAV (%)
Nicholls S. et al. JAMA. 2007;297:

15. Impact of HDL-C Raising on Plaque Progression
Pooled results from 6 major IVUS outcomes trials - 2 1
Increase in HDL (%) 10 20 30 40
Change
in PAV (%)
Nicholls S. et al. JAMA. 2007;297:

16. Total Atheroma Volume: LDL-C and HDL-C
2.1 mm3
0.2 mm3
-2.8 mm3
P < 0.001
Median LDL-C mg/dL
Median HDL-C change - 7.5%
-8.8 mm3
LDL-C worse
HDL-C worse
LDL-C worse
HDL-C better
LDL-C better
HDL-C worse
LDL-C better
HDL-C better

17. Other Potential Functions of HDL
Anti-inflammatory
Promote NO
Anti-oxidant
Anti-thrombotic

18. Lipid Filled Macrophage in Arteries
Current Working Model of HDL Metabolism
Liver
Intestine
LDLr
CETP CE TG
LDL
CD36 SR-A
SR-BI
ABCG1
A-I
αHDL
LCAT
ABCA1
Lipid Filled Macrophage in Arteries
A-I
αHDL
A-I
Preβ-HDL

19. CETP Inhibitors with Human Studies
Torcetrapib
Dalcetrapib
Anacetrapib
Evacetrapib
CF3
F3C N O S O HN O
F3C N F
CF3
Cao et al. J Lipid Res 2011; 52:2169 19

20. ILLUMINATE: Primary Endpoint: Time to First MACE: Kaplan-Meier Plot
100
Hazard Ratio 1.25
P=0.001 98 96
Event Free (%) 94 92
Atorvastatin events = 373
Torcetrapib/Atorvastatin events = 464 90 90
180
270
360
450
540
630
720
810
Days from Randomization
Barter et al, NEJM 2007;357:2109

21. Off Target Toxicity of Torcetrapib
Increase in BP even in animals that do not express CETP
Electrolyte changes consistent with RAAS activation
Increase adrenal synthesis of aldosterone and cortisol
Less nitric oxide synthase and greater endothelin expression associate with endothelial dysfunction

22. Illustrate Trial: Torcetrapib Change in Percent Atheroma Volume
This slide shows the results for the primary efficacy parameter, percent atheroma volume. After 24 months, the change was nearly identical in the two treatment groups, 0.19% in the atorvastatin monotherapy group and 0.12% in the torcetrapib-atorvastatin group, p = Thus, for the primary efficacy parameter, torcetrapib, despite a 61% relative increase in HDL-cholesterol and 20% relative decrease in LDL cholesterol, did not slow progression of coronary atherosclerosis.
Atorvastatin monotherapy
Torcetrapib- atorvastatin

23. Torcetrapib Results: Levels of HDL-C Achieved
Percent Atheroma Volume
Primary Efficacy Parameter
0.70%
0.30%
0.18%
P < 0.001
-0.69%
Quartile 1
<56 mg/dL
Quartile 2
56 to 69 mg/dL
Quartile 3
69 to 86 mg/dL
Quartile 4
>86 mg/dL

24. Dalcetrapib-OUTCOMES Trial
It was announced in early May 2012 that the dal-OUTCOMES trial had been terminated on the basis of futility.

25. Why Did Dalcetrapib Fail to Reduce CV Events?
Inhibiting CETP with a relatively weak inhibitor such as dalcetrapib may not be sufficient to have a favorable impact on CV events:
Only a 30% increase in HDL-C
No effect on LDL-C
However, we must acknowledge that CETP inhibition may not yield HDL-C particles with a favorable effect on CV morbidity and mortality.

26. Evacetrapib: Lipid Effects in Phase II Trial
Change in HDL-C
Change in LDL-C
Plac
30 mg
100 mg
500 mg

27. Resverlogix: ApoA-I Induction in CAD Patients
Parameter
Placebo (n=74)
RVX-208
P Value
100 mg (n=76)
200 mg (n=75)
300 mg (n=74)
ApoA-I
0.9
0.1
3.8
5.6
0.02
HDL-C
3.2
6.3*
8.3**
Large HDL
-0.5
11.1
20.2**
21.1***
0.003
Small HDL
2.6
-0.4
-2.6
-4.0
0.07
α1 HDL
-2.3
3.7
8.0*
8.8*
0.12
* P<0.05, ** P<0.01 and *** P<0.001compared with placebo
Nicholls JACC 2010; 57:1111-9