Residual risk and HDL-cholesterol: - PowerPoint Presentation

Slide1

Residual risk and HDL-cholesterol:What are the current perspectives?

Prof.

Erik

Stroes

Academic Medical Centre

Amsterdam, The Netherlands

Slide2

Is There a Therapeutic Need

Beyond LDL Lowering ?

1. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; 2. Shepherd J et al. N Engl J Med. 1995;333:1301-1307; 3. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; 4. Sever PS et al. Lancet. 2003;361:1149-1158; 5. Colhoun HM et al. Lancet. 2004;364:685-696.

Reduction in major coronary events vs placebo (%)

Potential for further risk reduction

WOSCOPS

2

-31

‡

4S

3

-34

†

ASCOT-LLA

4

-36

†

-36

†

HPS

1

-27

†

CARDS

5*

-37

‡

-40

-20

0

-60

-80

Percent

Slide3

The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000

Selecting ‘promising’ candidates

Based on Epidemiology

1.0

2.0

3.0

Hazard Ratio

40

60

80

HDL-C (mg/

dL

)

N = 302,430

30

50

70

Slide4

Shape

Density and size

Electrophoretic mobility

Apolipoprotein composition

Discoidal HDL

Spherical HDL

HDL2b

HDL2a

HDL3a

HDL3b

HDL3c

Diameter (nm)

10.6

7.6

LpA-I

LpA-I:A-II

Pre-β-1

α4

α3

α2

α1

Origin

Pre-β

migration

α

migration

Density (g/mL)

1.063

1.21

Pre-β-2

Pre-β-3

HDL2

HDL3

Camont L, et al.

Trends Mol Med.

2011;17(10):594-603.

HDL(-c) is ‘a mixed bag’

Cholesterol

concentration versus ‘particle’

Slide5

Kontush

A,

Nature CPCM 2008

Many ways to increase HDL-cPre-β-HDLPeripheral cell

ABCA1

HDL3

Lipid-free A-I

HDL2

FC, CE

PLTP HL

EL

Hepatocyte

A-I

LCAT

LCAT

SR-BI

CE

FC

FC

CE

Intestine

ABCG1

FC, PL

HDL-R

LDL-R

VLDL

VLDL-R

IDL

LDL

CETP

CE

CE

FC, CE

TG

TG

Production

Maturation

Remodeling

Clearance

Slide6

Outline

HDL-c and CV-protection

Protective mechanisms

Epidemiology versus GeneticsLessons learnt from HDL-c increasing trialsThe future for interventions targeting HDL-c

Slide7

Quantity versus Quality

QUANTITY

HDL-C / Apo AI

Chapman MJ. Pharmacol Rev. 2006.

Reverse cholesterol transport ‘cholesterol carrier’

QUALITY

Particle structure

Functionality

Other effects

‘carrier platform’

Slide8

HDL

Increases

Cholesterol Flux:Whole-body

and ‘Vascular’Eriksson, Circ 1999Shaw,

Circ Res 2008

Intestinal Excretion mg/day

Bile Acids

Neutral Sterols

SG

GG

LM

IN

0.0

100

200

300

400

Before Infusion

HDL-C (mg/dl)

41±7

After

Infusion

35% peak

Increase

Slide9

“Control” “Carrier of

APOA1

Static versus Dynamic

13C-cholesterol Tracer Dilution

FluxDe

Goma, Rader, JACC 2008

Slide10

HDL

protection

beyond RCTHDL increase

Vascular protection

Endothelial

Function

(Endothelial cell NO

production)

Anti-oxidant

effects

(Endothelial cell

superoxide production)

Anti-inflammatory

effects

(Endothelial cell

inflammatory activation)

Anti-

thrombotic

effects

REVERSE

CHOLESTEROL

TRANSPORT

Slide11

HDL Improves Endothelial Function

in ABC-A1

Heterozygotes

Bisoendial RJ, Stroes El. Circulation 2003Restoration ofEndothelial Function

Nieuwdorp, Stroes E, Diabetologia 2008

Slide12

Phospholipids

Triglycerids

Esterified cholesterol

Free

cholesterol

> 1000 different

lipids

(

Phospholipid

species

,

Cholesterol

Ester,

Trigylcerides

, …)

Cholesterol

Ester

HDL:

carrier

or

carrier-‘platform

‘ ?

Apo

A1

70 different

proteins

(ApoA1

,

PON-1,

ApoA2,

ApoCIII

,

ApoE

,

ApoH

, ….)

PON-1

Slide13

Summary I

protective mechanisms

HDL is both

‘cholesterol acceptor’ ‘carrier’ of enzymes/proteinsHDL can lose its ‘protective’ effects ‘Best test’ for HDL-quality and‘relevance’ of HDL-quality for CV-risk  Unknown

Slide14

Epidemiology versus Genetics

LDL

vs

HDLVoight, Lancet 2012

OR per SD increase in plasma lipid Observational epidemiology*

OR per SD increase

in plasma lipid Genetic score**

LDL-c

HDL-c

1.54

(1.45-1.63)

0.62 (0.58-0.66)

2.13 (1.69-2.69) p=2x10

-10

0.93 (0.68-1.26)

, p=0.63Observational epidemiology estimates derived from more than 25 000 individuals from prospective cohort studies as shown in the appendix p 22.

** LDL genetic score consisting of 13 single necleotide polymorphisms (SNPs) as shown in the appendix p 27;

HDL genetic score consisting of 14 SNPs as shown in the appendix p 28.

We confirm

that genetically raised plasma HDL cholesterol is not associated with risk of myocardial infarction.

A genetic score consisting of these 14 variants was not associated with risk of myocardial infarction. These results show that some ways of raising HDL cholesterol might not reduce risk of myocardial infarction in human beings.

Slide15

Summary II

Epidemiology

vs

GeneticsOverall, genetic HDL-c changes not related to risk:6 HDL-related variants do associate with riskExtreme genetic HDL-phenotypes associate with risk

Whereas the impact of HDLc on risk is evident,

the effect of ‘raising’ HDLc

might not invariably reduce risk of MI

Slide16

AIM-HIGH:

Niacin

ILLUMINATE:

Torcetrapibdal-OUTCOMES: Dalcetrapib ‘Negative’ HDLc trials Revisited

Slide17

AIM

HIGH:

Atherothrombosis

Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health OutcomesSimvastatin

40 mg + ER niacin 2 g

Simvastatin

40 mg

3300 patients

Primary End Point

Composite

of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk ACS with objective evidence of ischemia

Key Secondary End Points

Composite of CHD death, nonfatal MI, or ischemic stroke

Men and women

Aged



45 years

Established vascular disease and

atherogenic

dyslipidemia

(low HDL-C and high triglycerides)

4-year follow-up

clinicaltrials.gov/ct/show/NCT00120289

Slide18

Powered to detect 25% reduction in CV events

LDL-c in placebo group ‘titrated’ to <1.8mmol/l

(adding

ezetimibe / increasing statin dose)On-treatment difference in HDL-C 4 mg/dL (~ 4% event reduction)

Overall conclusion (

Nissen et al)

 ‘no consequences for clinical practice’

AIM-HIGH

Boden et al. N Eng J Med 2011; 356:2255

Slide19

ILLUMINATE

:

Primary Endpoint:

Time to First MCVE*: Kaplan-Meier Plot

*Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina

0

90

180

270

360

450

540

630

720

810

Days from Randomization

Event Free (%)

90

92

94

96

98

100

Atorvastatin (A) events = 373

Torcetrapib/Atorvastatin (T/A) events = 464

P=0.001

Hazard Ratio 1.25

Barter et al, NEJM 2007;357:2109

Slide20

Reasons for adverse outcome

with

Torcetrapib

Inhibiting CETP is wrong: wrong ‘pathway’ to increase HDL-c ? Inhibition of CETP generates ‘dysfunctional’ HDL ?

Torcetrapib is wrong off-target effects unrelated to CETP

Slide21

- increases aldosterone / cortisol

 increases blood pressure

- reduces eNOS, - increases ET-1 induces endothelial dysfunction

Other CETP inhibitors do not have these off-target effects

Forrest et al. Br J Pharmacol

. 2008;154:1465-1473). Hu et al. Endocrinology 2009;150:2211-2219.

Capponi et al. Circulation 2008;118:S:452. Connelly et al. J Cardiovasc Pharmacol 2010; 55:459.

Simic et al. Eur Heart J. 2012 (in press)

Off-target effects of

Torcetrapib

Slide22

15,600 patients 4-12 weeks after an index ACS event

Dal

-OUTCOMES

Trial

Dalcetrapib 600

mg

Statin therapy

to optimal

LDL-C level

Placebo

Primary End Point

CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest

2.5-year follow-up

Schwartz et al. Am Heart J. 2009;158:896.

Slide23

Explanations ?

weak

inhibitor, hence no impact on CV events CETP inhibition pro-atherogenic

HDL-C increase no valid target

Why did dalcetrapib fail

to reduce CV events?

Slide24

Other CETP-Inhibitors ?

Changes of lipid-parameters in %

Torcetrapib

* 60 mg/d Pfizer*Dalcetrapib* 600 mg/d Roche

Anacetrapib

100 mg/d MSD

Evacetrapib

500 mg/d Lilly

Total

chol

LDL-cTriglycerides

Apo BHDL-cApoA1

Lp

(a)

+ 4- 24- 9

- 12+ 61+ 25

+ 8

- 2

- 3

+ 4+ 31

+ 11-7

+ 16

- 40- 7

- 21+ 138+ 45

- 38

+ 11

- 40- 20

- 26+ 132

+ 50

* Clinical development program of

Torcetrapib

&

Dalcetrapib

stopped

Cannon C, JAMA 2011;306:2153

HaltedToxicity

Halted

FutilityOngoing

Reveal

Slide25

30,000 patients with occlusive arterial disease in North America, Europe and Asia

Background LDL-lowering with

atorvastatin

Randomized to anacetrapib 100 mg vs. placeboPrimary outcome: Coronary death, myocardial infarction or coronary revascularization

www.revealtrial.org.

Future

Slide26

Summary III

Lessons

HDLc-increasing trials

Trials to date haven’t solved the question whether HDL should be a therapeutic targetLessons we did learn:Power adequately with realistic ‘benefit’

AIM-HIGH failedWatch out for adverse effects prior to endpoint trial

Torcetrapib failed

Test the compound, not the mechanism

AIM-HIGH

Slide27

hyperTGemia

Omega-3 FAs

Reconstituted

apoAI/HDL ;

HDL delipidation

pre-

β

HDL

HDL

apoCIII

ABCA1 induction /

LXR agonists

Therapies

on the Horizon

sPLA2

HL

EL

LCAT

SR-B1

ApoAI

upregulation

ApoAI

mimetics

Niacin analogues

CETP Inhibitors

PPAR

agonists

apoAII

apoE

ApoAI upregulation

Slide28

Targeting cholesterol ‘flux’

by increasing

ApoA-I

7ABC-A1

Cytoplasm

Nucleus

Hepatocyte

ApoA-I Gene

ApoA-I

Protein

Phospholipids

Cholesterol

HDL

ApoA-I mRNA

RVX-208

Target

rHDL

CER001

Slide29

Re-events after ACS

Days

Indications for ‘

apo

-AI/HDL

infusables

’

‘Therapeutic gap’

after ACS

‘Lipid-rich’ core

depletion

Anti-inflammatory

Targeted delivery

cholesterol

Slide30

Take

Home:

In CVRM:

measure HDLc for risk-scoring (1C)Treat LDLc more vigorous in case of low HDLc (1C)If HDLc is low in high risk:consider adding nicotinic acid (2A)Validity of co-targeting HDL-c will be revealed < 3-4 years (HPS2/Reveal)Research foci in HDLc:Concentration vs Quality / Flux‘Where’ to intervene

(production/remodeling/clearance)How to measure succes (PET-CT / MRI)