1. University of Pennsylvania
HDL: Still a target for therapy? PaACC Annual Chapter Meeting November 2, 2008
Daniel J. Rader, MD
University of Pennsylvania
School of Medicine

2. Lipoproteins and Atherosclerosis Oxidation, modification, aggregationCE B
Chol
Chol
Arterial macrophage
LDL

3. LDL goals keep going down
Moderately High Risk
≥2 risk factors
(10-yr risk 10–20%)
High Risk
CHD or CHD risk equivalents
(10-yr risk >20%)
Moderate Risk
≥2 risk factors
(10-yr risk <10%)
Lower Risk
<2 risk factors
190 -
goal
160
mg/dL
160 -
goal
130
mg/dL
goal
130
mg/dL
LDL-C level
130 -
goal
100
mg/dL
100 mg/dL*
Based on recent clinical trial evidence, an NCEP report1 has been published recommending tighter control of cholesterol management. The trials support an LDL-C goal of <100 mg/dL in high-risk patients, and the inclusion of diabetes in the high-risk category. All patients with CHD or CHD risk equivalents are at high-risk. Therapeutic lifestyle changes (TLC) remain an essential part of clinical management.
In patients at high risk (CHD and CHD risk equivalents, 10-year risk >20%), the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL (1.8 mmol/dL) is a proposed therapeutic option. Patients at very high risk are those with established CVD plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (especially continued cigarette smoking); multiple risk factors of the metabolic syndrome and patients with acute coronary syndrome. The recommended point at which TLC should be initiated is an LDL-C level of 100 mg/dL (2.6 mmol/L). The guidelines recommend that drug therapy be considered in this category simultaneously with TLC in persons whose LDL-C levels are 100 mg/dL (2.6 mmol/L).
In patients at moderately high risk (2 risk factors and 10-year CHD risk of 10–20%) the guidelines recommend that TLC are initiated at LDL-C levels of 130 mg/dL (3.4 mmol/L), with the aim of <130 mg/dL (3.4 mmol/L), but an LDL-C goal of <100 mg/dL (2.6 mmol/L) is a therapeutic option based on clinical trial evidence. This also applies to patients with a baseline LDL-C of mg/dL. Drug therapy should be considered if LDL-C levels remain 130 mg/dL (3.4 mmol/L), after 3 months of TLC.
In patients at moderate risk (2 risk factors and 10-year CHD risk of <10%) the guidelines recommend that TLC are initiated at LDL-C levels of 130 mg/dL (3.4 mmol/L), with the aim of <130 mg/dL (3.4 mmol/L). In this group drug therapy should be considered at LDL-C levels 160 mg/dL (4.1 mmol/L).
In individuals at lower risk (<2 risk factors) and whose LDL-C levels are 160 mg/dL (4.1 mmol/L), TLC are recommended. Drug therapy should be considered when LDL-C levels are 190 mg/dL (5 mmol/L) despite TLC, and is optional depending on clinical judgement at LDL-C levels of 160–189 mg/dL (4.1-5 mmol/L). The goal for LDL-C in this risk category is <160 mg/dL (4.1 mmol/L).
When LDL-C lowering drug therapy is employed in high-risk or moderately high-risk patients, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has life-style related risk factors (eg obesity, physical inactivity, elevated TG, low HDL-C or the metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level.
Reference
1. Grundy SM, Cleeman JI, Merz NB et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239.
Previous LDL-C goals
New LDL-C goals
100 - 70
mg/dL*
70 -
Grundy SM, et al. Circulation. 2004;110:

4. TNT: Stable CAD Patients Major Cardiovascular Events
(HR = % CI 0.69, 0.89)
P=0.0002
Proportion of patients experiencing major cardiovascular event
0.05
0.10
0.15
Atorvastatin 10 mg LDL 100
Atorvastatin 80 mg LDL 77
Time (years)
Relative risk reduction = 22%
Over the course of the study, there was a highly significant reduction in major cardiovascular events in the atorvastatin 80mg group. The Kaplan-Meier analysis demonstrates a hazard ratio of 0.78 with a p-value of
This represents a 22% reduction in relative risk in the atorvastatin 80mg group relative to the atorvastatin 10 mg group over-and-above the remarkably low absolute event rate of 10.9% recorded in the atorvastatin 10mg group.
There was no statistical interaction for age or gender in the primary outcome measure. Further analyses of these categories are underway.
*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke
LaRosa JC, et al. N Eng J Med. 2005;352

5. Lipoproteins and Atherosclerosis Oxidation, modification, aggregation
A-I
Oxidation, modification, aggregation CE CE CE B
Chol
HDL
Arterial macrophage
LDL

7. “On-treatment” HDL-C Predicts Cardiovascular Events: TNT
Major Cardiovascular Events
On treatment HDL-C (mg/dL) %
Mean LDL-C 99 mg/dL
Mean LDL-C 73 mg/dL
Barter et al. ACC Abstract

8. Is HDL causally related to atherosclerosis and CHD risk or simply a very good integrator and biomarker of CHD risk?

9. Low HDL is often accompanied by other cardiovascular risk factors
Insulin resistance
Inflammation
Hypertension
High triglycerides
↓HDL
Gerald Reaven in 1988 coined the term
Jean-Pierre Despres in Quebec
↑ Cardiovascular Disease

10. Low HDL is often accompanied by other cardiovascular risk factors
Insulin resistance
Inflammation
Hypertension
High triglycerides
↓HDL
Gerald Reaven in 1988 coined the term
Jean-Pierre Despres in Quebec ?
↑ Cardiovascular Disease

11. Hepatic expression of apoA-I reduces and even regresses atherosclerosis in mice
AdapoA-I
Liver
A-I
HDL

12. HDL Metabolism and Reverse Cholesterol Transport
Bile
A-I
A-I FC CE CE FC
LCAT FC FC CE
ABCA1
SR-BI
Macrophage
Liver

13. Quantitation of macrophage to feces reverse cholesterol transport in vivo
3H-BA
3H-FC
Bile
3H-BA
3H-FC
3H-Chol
3H-BA
3H-FC
Plasma
3H-cholesterol,
AcLDL
3H-chol

14. ApoA-I overexpression promotes macrophage to feces reverse cholesterol transport
ApoA-I adenovirus
Feces
3H-BA
3H-FC
Bile
3H-BA
3H-FC
3H-Chol
3H-BA
3H-FC
Plasma
3H-cholesterol,
AcLDL
3H-chol

15. HDL-C levels are not a marker of the rate of reverse cholesterol transport
Bile
A-I
A-I FC CE CE FC
LCAT FC FC CE
ABCA1
SR-BI
Macrophage
Liver
SR-BI HDL RCT atherosclerosis
Zhang, et al, J Clin Invest, 2004

16. Targeting HDL metabolism for therapeutic reasons is complex
Intestine
ABCG1
A-I
A-I FC
PPARα
PPARγ
PPARδ BA
LXR FC FC
LCAT FC FC CE
ABCA1
SR-BI
HL, EL M
Macrophage
Liver
CETP
LDLR
PLTP CE B TG
Anti-oxidant, anti-inflammatory, anti-thrombotic, other
VLDL/LDL

17. Clinical studies have not definitively confirmed the HDL hypothesis
Niacin: Coronary Drug Project, HATS
Fibrates: VA-HIT, BIP, FIELD
ApoA-I: IVUS studies

18. Nicotinic Acid (Niacin)
This is its structure.

19. Niacin acts on adipose to reduce FFA release and flux to liverB
VLDL
apoB
MTP TG
LDLR B
FFA
LDL
FFA
Niacin

20. Niacin receptor (GPR109A)
Highly expressed in adipose tissue
Mediates the anti-lipolytic effects of niacin

21. Adipocyte lipolysis generating FFA
Adenylate
Cyclase
ATP
cAMP
FFA
PKA
Inactive
HSL
Active
HSL TG
FFA

22. Suppression of lipolysis in adipocytes by niacin activating its receptor GPR109A
Gi-GDP
Gi-GTP
Adenylate
Cyclase
ATP
cAMP
FFA
PKA
Inactive
HSL
Active
HSL TG
FFA

23. Niacin activates its receptor GPR109A in adipose to reduce FFA release and flux to liver
LDLR
apoB TG B
VLDL
LDL
MTP
FFA
Niacin
GPR109A

24. Mechanism of Niacin-induced Flushing
Nicotinic Acid–Induced Flush
Undesirable effects
Arachidonic acid
COX-1
EP2 or EP4
DP1
Smooth muscle cell or other cell type
Dermal macrophages
PGE2
PGD2
Cutaneous vasodilation and burning sensation on face and upper body
Adapted from Pike NB. J Clin Invest. 2005;115:

25. Mechanisms of niacin’s HDL raising effects?CE ? PL TG
Liver
Kidney

26. Data are needed proving that adding niacin to a statin reduces CV outcomes to a greater extent than statin alone

27. AIM-HIGH Study Overview
Simvastatin
Atherogenic Dyslipidemia
(HDL<40 or 50; TGL>149; LDL<160)
CV Death
NFMI
Stroke
ACS
3-5 yr
Vascular Dz.
Age >45 years
Simvastatin + niaspan
2 year enrollment
Hypothesis
-30% event rate
with Simva
-23% event rate with simva-nia
- 50% relative reduction based on ~46% placebo rate
3300 patients from 60
sites (U.S. and Canada
LDL-C target <80 mg/dl both groups (may add ezetimibe if needed)

28. HPS2-THRIVE: A Randomized Trial of the Long-term Clinical Effects of Raising HDL With Niacin and Laropiprant
Does niacin combined with Laropiprant prevent vascular events
in high-risk patients receiving intensive LDL-lowering therapy?
An international
collaboration, with a Central Office in Oxford and 3 Regional Coordinating Centers in the UK, China and Scandinavia, will conduct the trial in about 200 hospitals
Patients aged years with pre-existing
atherosclerotic disease receiving
simvastatin 40 mg qd and, if indicated,
ezetimibe/simvastatin 10/40 mg qd
N=20,000
Randomization
Niacin 2 g +
Laropiprant 40 mg
Placebo
Follow-up visits at 3 and 6 months,
then every 6 months thereafter
THRIVE=Treatment of HDL to Reduce the Incidence of Vascular Events.

29. CETP inhibition: the definitive test of the HDL hypothesis?

30. HDL Metabolism: Role of CETP
Bile
A-I
A-I FC CE CE FC
LCAT FC FC CE
ABCA1
SR-BI
Macrophage
Liver
CETP
LDLR CE B TG
VLDL/LDL

31. CETP Deficiency is Associated with Markedly Increased HDL-C Levels
A-I
Bile FC
A-I FC CE CE CE
LCAT FC FC
ABCA1
SR-BI
Macrophage
Liver X
CETP
LDLR CE B TG
VLDL/LDL

32. CETP Inhibition as a Novel Strategy to Raise HDL-C
Bile
Feces
A-I
A-I FC CE CE FC
LCAT FC CE FC
ABCA1
SR-BI
Macrophage
Liver X
CETP
LDLR
CETP inhibitor CE B TG
VLDL/LDL

33. Treatment with the CETP inhibitor torcetrapib substantially raiseed HDL-C levels in patients with low HDL
Brousseau, et al. NEJM 350: ; 2004

35. ILLUMINATE: Increased mortality and major cardiovascular events in subjects randomized to torcetrapib therapy despite favorable lipid changes
HDL 72%
LDL 25%
Figure 2. Kaplan-Meier Curves for Death from Any Cause and for the Primary Composite Outcome. Panel A shows the between-group comparison of patients who died from any cause during the study: 59 patients in the atorvastatin-only group and 93 patients in the torcetrapib group. Panel B shows the between-group comparison of patients who had the primary composite outcome: 373 patients in the atorvastatin-only group and 464 patients in the torcetrapib group. The primary outcome was the time to the first occurrence of a major cardiovascular event, a composite that included four components: death from coronary heart disease, nonfatal myocardial infarction (excluding procedure-related events), stroke, and hospitalization for unstable angina. Analyses in both panels were censored on December 2, 2006.
Barter P et al. N Engl J Med 2007

36. Torcetrapib Phase III Imaging Program: Efficacy
One coronary IVUS and two carotid IMT trials
Torcetrapib resulted in increases in HDL-C of 50-63% and decreases in LDL-C of ~ 20%
No significant impact on atherosclerosis progression by carotid IMT or coronary IVUS

37. Torcetrapib Phase III Imaging Program: Blood pressure
Carotid IMT trial in heterozygous FH patients (RADIANCE 1): Mean BP increase 2.1 mmHg
Carotid IMT trial in mixed hyperlipidemia (RADIANCE 2): Mean BP increase 5.1 mmHg
Coronary IVUS study in CHD patients (ILLUSTRATE): Mean BP increase 4.6 mmHg

38. Is the BP increasing effect of torcetrapib
- a mechanism-based effect of CETP inhibition
-or a molecule-specific effect of torcetrapib?

39. ILLUMINATE: Increased mortality and major cardiovascular events in subjects randomized to torcetrapib therapy
Table 4. Causes of Death.
Barter P et al. N Engl J Med 2007

40. Potential Mechanisms of Adverse Outcomes Associated with Torcetrapib
Figure 1. Potential Mechanisms of Adverse Outcomes Associated with Torcetrapib. Treatment with torcetrapib has both mechanism-based and off-target effects that may have contributed to an increased rate of adverse cardiovascular and noncardiovascular outcomes. The drug inhibits cholesteryl ester transfer protein (CETP), blocking the transfer of cholesteryl esters to lipoproteins containing apolipoprotein B (ApoB), such as low-density lipoprotein (LDL), resulting in increased levels of high-density lipoprotein (HDL) cholesterol and enlarged HDL particles. Although HDL cholesterol can be taken up directly by the liver through the HDL scavenger receptor, class B, type I (SR-BI), inhibition of CETP may reduce the rate of return of HDL cholesterol to the liver, thus impairing reverse cholesterol transport and increasing cardiovascular risk. In addition, the change in HDL composition could conceivably impair immune function associated with HDL, thus increasing noncardiovascular risks such as infection and cancer. On the other hand, the molecule torcetrapib clearly has the off-target effects of elevating levels of aldosterone and blood pressure, changes that probably contributed to the increased cardiovascular risk. The potential that torcetrapib has off-target effects that contributed to an increased risk of noncardiovascular events is possible but speculative. Finally, CETP inhibition has the potentially beneficial effects of increasing cholesterol efflux from macrophages mediated by ATP-binding cassette transporter G1 (ABCG1) (which could increase the rate of physiologically relevant reverse cholesterol transport from macrophages) and of increasing the uptake of LDL cholesterol by the liver (which reduces LDL cholesterol levels), effects that could be important for CETP inhibitors that do not have the off-target effects of torcetrapib.
Rader D. N Engl J Med 2007

41. Could CETP inhibition impair reverse cholesterol transport?
Bile
Feces
A-I
A-I FC CE CE FC
LCAT FC CE FC
ABCA1
SR-BI
Macrophage
Liver X
CETP
LDLR
CETP inhibitor CE B TG
VLDL/LDL

42. Potential beneficial effects of CETP inhibition
Bile
Feces
ABCG1
A-I
A-I FC CE CE FC
LCAT FC CE FC
ABCA1
SR-BI
Macrophage
Liver X
CETP
LDLR
CETP inhibitor CE B TG
VLDL/LDL

43. HDL-targeted therapeutics in the post-torcetrapib era: focus on HDL function
Increasing HDL-C levels is neither adequate nor necessary for predicting cardiovascular benefit of an HDL-targeted therapeutic approach Improving HDL function will be the focus of new therapies Better and standardized methods to assess HDL function will be required

44. Targeting HDL: Promote Reverse Cholesterol Transport
Bile
A-I
A-I FC CE CE FC
LCAT FC FC CE
ABCA1
SR-BI
Macrophage
Liver

45. Increasing lipid-poor apoA-I as an acceptor for cholesterol efflux via ABCA1BA FC FC
LCAT FC FC CE
ABCA1
SR-BI
Macrophage
CETP
LDLR CE B TG
VLDL/LDL

46. Increasing lipid-poor apoA-I as an acceptor for cholesterol efflux: parenteral approaches
ApoA-I Milano/phospholipid complexes
ApoA-I (wild-type)/PL complexes
ApoA-I mimetic peptides
Large unilamellar vesicles (LUVs)
Delipidated HDL

47. Increasing endogenous apoA-I production via transcriptional enhancement
Liver
Intestine
A-I
HDL

48. Regulation of Cholesterol Efflux in the Macrophage by LXR
A-I CE
ABCG1
LXR
Chol
A-I
ABCA1

49. Pharmacologic Promotion of Macrophage Cholesterol Efflux by Synthetic LXR Agonists
A-I CE
ABCG1
LXR
Chol
A-I
ABCA1
Agonist

50. The LXR agonist GW3965 significantly increased macrophage to feces reverse cholesterol transport in vivo
2.5 *
2.0
% CPM Injected
1.5
1.0
0.5
0.0
Control
LXR agonist
Naik, et al, Circulation 2005

51. LXR agonists can cause steatosis, hypertriglyceridemia, and elevated LDL-CTG B
VLDL
apoB
MTP TG
LDLR B
LDL
SREBP1c
LXR

52. Endothelial Lipase: a member of the lipoprotein lipase gene family
TG-rich lipoproteins
HDL TG
Lipase
LPL HL EL
Phospholipase
Jaye M, et al, Nature Genetics 21:424; 1999

53. Endothelial lipase promotes catabolism of apoA-I and reduces HDL levels
Bile
A-I
A-I FC EL CE CE
SR-BI PL TG
Liver
Kidney

54. Endothelial lipase is upregulated by inflammation in metabolic syndrome and mediates low HDL-C levels
Cytokines
↑EL
Gerald Reaven in 1988 coined the term
Jean-Pierre Despres in Quebec
↓HDL

55. Mutations in endothelial lipase cause high HDL

56. Endothelial Lipase: Target for Pharmacologic Inhibition to Raise HDL?
EL inhibitor
Bile
A-I
A-I FC X EL CE CE
SR-BI PL TG
Liver
Kidney

57. Targeting HDL metabolism for therapeutic reasons is complex
Intestine
ABCG1
A-I
A-I FC
PPARα
PPARγ
PPARδ BA
LXR FC FC
LCAT FC FC CE
ABCA1
SR-BI
HL, EL M
Macrophage
Liver
CETP
LDLR
PLTP CE B TG
Anti-oxidant, anti-inflammatory, anti-thrombotic, other
VLDL/LDL