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

HDL: Still a target for therapy?

PaACCAnnual Chapter Meeting

November 2, 2008

Daniel J. Rader, MDUniversity of Pennsylvania

School of [email protected]

Lipoproteins and Atherosclerosis

Chol

Arterial macrophage

B

LDL

Chol

Oxidation, modification, aggregation

CE

LDL goals keep going down

Grundy SM, et al. Circulation. 2004;110:227-239.

High Risk

CHD or CHD risk equivalents

(10-yr risk >20%)

LD

L-C

lev

el

100 -

160 -

130 -

190 -

Lower Risk

<2 risk factors

Moderately High Risk

≥2 risk factors

(10-yr risk 10–20%)goal

160mg/dL

goal

130mg/dL

70 -

goal

100 mg/dL

70 mg/dL*

Moderate Risk

≥2 risk factors

(10-yr risk <10%)

goal

130 mg/dL

100 mg/dL*

Previous LDL-C goals

New LDL-C goals

TNT: Stable CAD PatientsMajor Cardiovascular Events

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

(HR = 0.78 95% CI 0.69, 0.89)P=0.0002

Pro

po

rtio

n o

f p

atie

nts

exp

erie

nci

ng

m

ajo

r ca

rdio

vasc

ula

r ev

ent

0

0.05

0.10

0.15

Atorvastatin 10 mg LDL 100 LDL 100

Atorvastatin 80 mg LDL 77LDL 77

0 1 2 3 4 5 6Time (years)

Relative risk

reduction = 22%

LaRosa JC, et al. N Eng J Med. 2005;352

Lipoproteins and Atherosclerosis

Chol

Arterial macrophage

B

LDL

CE

Oxidation, modification, aggregation

CE

HDL

A-I

CE

0

2

4

6

8

10

12

14

Atorva 10 Atorva 80

<40

>40-50

>50-60

>60

On treatmentHDL-C (mg/dL)

Barter et al. ACC 2006. Abstract 914-203.

Major Cardiovascular Events

%

Mean LDL-C73 mg/dL

Mean LDL-C99 mg/dL

“On-treatment” HDL-C Predicts Cardiovascular Events: TNT

Is HDL causally related to atherosclerosis and CHD risk

or simply a very good integrator and biomarker of CHD risk?

Low HDL is often accompanied by other cardiovascular risk factors

Insulin resistanceInflammationHypertensionHigh triglycerides

↑ Cardiovascular Disease

↓HDL

Low HDL is often accompanied by other cardiovascular risk factors

Insulin resistanceInflammationHypertensionHigh triglycerides

↑ Cardiovascular Disease

↓HDL

?

Hepatic expression of apoA-I reduces and even regresses atherosclerosis in mice

Liver

A-I

HDL

AdapoA-I

HDL Metabolism and Reverse Cholesterol Transport

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEFC

Quantitation of macrophage to feces reverse cholesterol transport in vivo

Plasma 3H-cholesterol,AcLDL

3H-CholBile

Feces

3H-FC

3H-chol

3H-BA

3H-BA

3H-BA 3H-FC

3H-FC

ApoA-I overexpression promotes macrophage to feces reverse cholesterol transport

Plasma 3H-cholesterol,AcLDL

3H-CholBile

Feces

3H-FC

3H-chol

3H-BA

3H-BA

3H-BA 3H-FC

3H-FC

ApoA-I adenovirus

HDL-C levels are not a marker of the rate of reverse cholesterol transport

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEFC

SR-BI HDL RCT atherosclerosis

SR-BI HDL RCT atherosclerosis

Zhang, et al, J Clin Invest, 2004

A-I

Liver

CE FCFCLCAT

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

TG

FC

ABCG1

FCLXRLXR

PPARαPPARγPPARδFC

BA

PLTP

HL, EL M

Intestine

Anti-oxidant, anti-inflammatory, anti-thrombotic, other

Targeting HDL metabolism for therapeutic reasons is complex

Clinical studies have not definitively confirmed the HDL hypothesis

• Niacin: Coronary Drug Project, HATS

• Fibrates: VA-HIT, BIP, FIELD

• ApoA-I: IVUS studies

Nicotinic Acid (Niacin)

N

C

O

OH

LDLR

apoB

TG

BVLDL

BLDL

Niacin acts on adipose to reduce FFA release and flux to liver

MTP

FFA

FFA

Niacin

Niacin receptor (GPR109A)

• Highly expressed in adipose tissue

• Mediates the anti-lipolytic effects of niacin

Adipocyte lipolysis generating FFA

ATP cAMP

AdenylateCyclase

InactiveHSL

Active HSL

PKA

FFA

FFA

TG

Suppression of lipolysis in adipocytes by niacin activating its receptor GPR109A

GPR109A

Gi-GDP

Niacin

Gi-GTP

ATP cAMP

AdenylateCyclase

InactiveHSL

Active HSL

PKA

FFA

FFA

TG

Niacin activates its receptor GPR109A in adipose to reduce FFA release and flux to liver

LDLR

apoB

TG

BVLDL

B LDL

MTP

FFA

FFA

Niacin

GPR109A

Mechanism of Niacin-induced Flushing

Adapted from Pike NB. J Clin Invest. 2005;115:3400-3403.

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

PGE2

PGD2

Cutaneousvasodilation and

burning sensationon face andupper body

A-I

Liver

CE

A-I

TG

Kidney

PL

Mechanisms of niacin’s HDL raising effects?

?

Niacin

Data are needed proving that adding niacin to a statin reduces CV outcomes

to a greater extent than statin alone

Vascular Dz.Age >45 years

Atherogenic Dyslipidemia (HDL<40 or 50; TGL>149; LDL<160)

Simvastatin

Simvastatin + niaspan

3-5 yr

3300 patients from 60 sites (U.S. and Canada

CV DeathNFMIStrokeACS

AIM-HIGHStudy Overview

LDL-C target <80 mg/dl both groups (may add ezetimibe if needed)

Hypothesis-30% event rate with Simva -23% event rate with simva-nia - 50% relative reduction based on ~46% placebo rate

2 year enrollment

HPS2-THRIVE: A Randomized Trial of the Long-term Clinical Effects of Raising HDL

With Niacin and Laropiprant

THRIVE=Treatment of HDL to Reduce the Incidence of Vascular Events.

Patients aged 50-80 years with pre-existing atherosclerotic disease receiving

simvastatin 40 mg qd and, if indicated,ezetimibe/simvastatin 10/40 mg qd

N=20,000

Niacin 2 g + Laropiprant 40 mg

Placebo

Randomization

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

Follow-up visits at 3 and 6 months, then every 6 months thereafter

Does niacin combined with Laropiprant prevent vascular events in high-risk patients receiving intensive LDL-lowering therapy?

CETP inhibition:

the definitive test of the HDL hypothesis?

HDL Metabolism: Role of CETP

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

CE

TG

FC

CETP Deficiency is Associated with Markedly Increased HDL-C Levels

Liver

CEFCFC

LCATFC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

CE

TG

A-I

CE

FC

XX

CETP Inhibition as a Novel Strategy to Raise HDL-C

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

CE

TG

FC

X

Feces

CETP inhibitor

Treatment with the CETP inhibitor torcetrapib substantially raiseed HDL-C levels in patients with low HDL

0

10

20

30

40

50

60

70

80

90

100

Untreated 120 mg 240 mg

HD

L C

ho

les

tero

l (m

g/d

l)

Brousseau, et al. NEJM 350:1505-1515; 2004

Barter P et al. N Engl J Med 2007

ILLUMINATE: Increased mortality and major cardiovascular events in subjects randomized to

torcetrapib therapy despite favorable lipid changes

HDL 72%LDL 25%

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

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

Is the BP increasing effect of torcetrapib

- a mechanism-based effect of CETP inhibition

-or a molecule-specific effect of torcetrapib?

Barter P et al. N Engl J Med 2007

ILLUMINATE: Increased mortality and major cardiovascular events in subjects randomized to

torcetrapib therapy

Rader D. N Engl J Med 2007

Potential Mechanisms of Adverse Outcomes Associated with Torcetrapib

Could CETP inhibition impair reverse cholesterol transport?

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

CE

TG

FC

X

Feces

CETP inhibitor

Potential beneficial effects of CETP inhibition

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

CE

TG

FC

X

Feces

CETP inhibitor

ABCG1

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

HDL-targeted therapeutics in the post-torcetrapib era:

focus on HDL function

Targeting HDL: Promote Reverse Cholesterol Transport

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEFC

A-I

CE FCFCLCAT

SR-BI

A-I

Macrophage

CEB

LDLR

VLDL/LDL

CETP

TG

FCFCBA

Increasing lipid-poor apoA-I as an acceptor for cholesterol efflux via ABCA1

ABCA1

• ApoA-I Milano/phospholipid complexes• ApoA-I (wild-type)/PL complexes• ApoA-I mimetic peptides• Large unilamellar vesicles (LUVs)• Delipidated HDL

Increasing lipid-poor apoA-I as an acceptor for cholesterol efflux:

parenteral approaches

Increasing endogenous apoA-I production via transcriptional

enhancement

A-I

LiverIntestine

HDL

Chol

A-I ABCA1

A-I

CEABCG1

Regulation of Cholesterol Efflux in the Macrophage by LXR

LXR

Chol

A-I ABCA1

A-I

CEABCG1

LXR

Agonist

Pharmacologic Promotion of Pharmacologic Promotion of Macrophage Cholesterol Efflux by Macrophage Cholesterol Efflux by

Synthetic LXR AgonistsSynthetic LXR Agonists

% C

PM

In

ject

ed

The LXR agonist GW3965 significantly The LXR agonist GW3965 significantly increased macrophage to feces reverse increased macrophage to feces reverse

cholesterol transport in vivocholesterol transport in vivo

0.0

0.5

1.0

1.5

2.0

2.5

*

Control LXR agonistNaik, et al, Circulation 2005

LDLR

apoB

TG

BVLDL

BLDL

LXR agonists can cause steatosis, hypertriglyceridemia, and elevated LDL-C

MTP

LXR

SREBP1c

TG

TGLipase

LPL HL EL

Phospholipase

TG-rich lipoproteins HDL

Endothelial Lipase: a member of the lipoprotein lipase gene family

Jaye M, et al, Nature Genetics 21:424; 1999

A-I

Liver

CECE

FC

Bile

SR-BI

A-I

TG

Kidney

PL

EL

Endothelial lipase promotes catabolism of apoA-I and reduces HDL levels

Endothelial lipase is upregulated by inflammation in metabolic syndrome

and mediates low HDL-C levels

Cytokines

↓HDL

↑EL

Mutations in endothelial lipase cause high HDL

A-I

Liver

CECE

FC

Bile

SR-BI

A-I

Endothelial Lipase: Target for Pharmacologic Inhibition to Raise HDL?

TG

Kidney

PL

EL

EL inhibitor

X

A-I

Liver

CE FCFCLCAT

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

TG

FC

ABCG1

FCLXRLXR

PPARαPPARγPPARδFC

BA

PLTP

HL, EL M

Intestine

Anti-oxidant, anti-inflammatory, anti-thrombotic, other

Targeting HDL metabolism for therapeutic reasons is complex