The future of HDL The future of HDL raisingraising

ByBy

Ashraf Reda M.D.Ashraf Reda M.D. Minoufiya UniversityMinoufiya University

President of: WGLVRPresident of: WGLVR

1

Bile

Reverse cholesterol transport

PeripheralTissue

LiverBlood

Excess cholesterol

HDL:

Ashraf Reda,M.D.6

CE

FC

Macrophage

ABC1

Nascent HDL from liver or intestine

FC

LCAT

A-1

Mature HDL

CESR-B1

CE

FC

Bile

CE= cholesterol ester; FC= free cholesterol; A-1= apolipoproteinA-1;ABC1= ATP-binding cassettte protein-1;LCAT= Lecithin:cholesterol acyl transeferase;SR-B1=scavenger receptor class B1

Reverse cholesterol transport and HDL metabolism

A-1

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HDLHDL Reverse cholesterol transport(Apo-A1Reverse cholesterol transport(Apo-A1

—ABC-A1)—ABC-A1) Inhibition of adhesion moleculesInhibition of adhesion molecules AntioxidentAntioxident Vasotonic effectVasotonic effect Prevent LDL oxidation and depositionPrevent LDL oxidation and deposition

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Ashraf Reda,M.D.

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1.6%++BP

9

BP increaseIn 1.6%

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Mortalityincrease

ILLUMINATE / ILLUSTRATE:ILLUMINATE / ILLUSTRATE: Torcetrapib increases CV end Torcetrapib increases CV end

pointspoints

Failure of HDL theory????Failure of HDL theory????

Failure of CETP inhibition????Failure of CETP inhibition????

OR

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11 + + 11 = = 11

HDL interacts with eNOS & NO HDL interacts with eNOS & NO secretionsecretion

Torcetrapib increases BPTorcetrapib increases BP

+

There must be a change in HDL function with Torcetrapib

CE

Mature HDL

Apo-A-1

CE

Apo-B

VLDL/LDL

CETP

Idea:Inhibition of CETP will

increase HDL availability and reduce LDL

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CE

FC

Macrophage

ABC1

Nascent HDL from liver or intestine

FC

LCAT

A-1

Mature HDL

CESR-B1

CE

FC

Bile

CE= cholesterol ester; FC= free cholesterol; A-1= apolipoproteinA-1;ABC1= ATP-binding cassettte protein-1;LCAT= Lecithin:cholesterol acyl transeferase;SR-B1=scavenger receptor class B1

Reverse cholesterol transport and HDL metabolism

A-1

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CEFC

Macrophage

ABC1Nascent HDL

from liver or intestine

FC

A-1

LCAT

A-1

Mature HDL

CESR-B1

CE

FC

Bile

VLDL/LDL

B

CETP

CE

LDLreceptor

HDL metabolism: Reverse cholesterol transport and the

role of CETP

Oxidation

SR-A

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ILLUMINATE / ILLUSTRATE:ILLUMINATE / ILLUSTRATE:Why do endpoints increased Why do endpoints increased

with Torcetrapib?with Torcetrapib?

Interaction with e-NOS lead to BP riseInteraction with e-NOS lead to BP rise Enlarged HDL with impaired interaction Enlarged HDL with impaired interaction

with SR-B1 of the liverwith SR-B1 of the liver Induction of Endothelin-1 secretionInduction of Endothelin-1 secretion Interfere with the reverse cholesterol Interfere with the reverse cholesterol

transporttransport

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CETP inhibition to raise HDL:CETP inhibition to raise HDL:is it the correct way to go?is it the correct way to go?

NONO

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There are many way There are many way to skin a fishto skin a fishWe also have many way to raise We also have many way to raise

HDLHDL

&

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Primary (genetic) causes of Primary (genetic) causes of low HDLlow HDL

Apo-A1:Apo-A1: Complete DeficiencyComplete Deficiency Mutation (Milano Apo-A1)Mutation (Milano Apo-A1)

LCATLCAT Complete deficiencyComplete deficiency Partial (fish eye disease)Partial (fish eye disease)

ABC-1ABC-1 Tangier disease (homo- or hetero- zygos)Tangier disease (homo- or hetero- zygos) Familial hypo alpha lipoproteinemiaFamilial hypo alpha lipoproteinemia

Unknown genetic A/EUnknown genetic A/E Metabolic syndromeMetabolic syndrome FCH with low HDLFCH with low HDL HypoalphalipoproteinemiaHypoalphalipoproteinemia

HDLA-1

Mature HDL

A-1

CE

FC

FC

ABC-1

Macrophage

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Ashraf Reda,M.D.

16

Other therapeutic ApproachesOther therapeutic Approaches

Milano type-apo A1 acutely increase HDLMilano type-apo A1 acutely increase HDL Over expression of LCATOver expression of LCAT ABCA1 activatorsABCA1 activators ETC-216: Recombinant Apo-A1 MilanoETC-216: Recombinant Apo-A1 Milano ETC-588:Phospholipid liposome ETC-588:Phospholipid liposome

(Cholesterol sponge)(Cholesterol sponge) Liver-X-receptors (LXR) agonistsLiver-X-receptors (LXR) agonists Endothelial Lipase inhibitors to prevent Endothelial Lipase inhibitors to prevent

Apo-A1 catabolismApo-A1 catabolism

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The current evidenceThe current evidence

Raising HDL is at least as important as Raising HDL is at least as important as reducing LDL in reducing coronary events reducing LDL in reducing coronary events and slowing atherosclerosis progression.and slowing atherosclerosis progression.

A strong statin +Niacin is the most effective A strong statin +Niacin is the most effective strategy.strategy.

Meta-analysis showed Meta-analysis showed >>60% RR with 60% RR with combination therapy compared with combination therapy compared with ++ 25% 25% with statin alonewith statin alone

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2009-2011:2009-2011:What Are We Waiting For?What Are We Waiting For?

ACCORD: Fenofib+statin Vs Statin in 9750 pts with ACCORD: Fenofib+statin Vs Statin in 9750 pts with DM2DM2

AIM-HIGH Simva +Niacepam Vs Simva in 3300 Pts AIM-HIGH Simva +Niacepam Vs Simva in 3300 Pts (Metabolic syndrome) with CVD, low HDL and high (Metabolic syndrome) with CVD, low HDL and high TAGTAG

Heart Protection Study 2 Treatment of HDL to Heart Protection Study 2 Treatment of HDL to

Reduce the Incidence of Vascular EventsReduce the Incidence of Vascular Events (HPS2- (HPS2-THRIVE)THRIVE)

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ConclusionsConclusions

CETP inhibition is a harmful strategyCETP inhibition is a harmful strategy Epidemiological studies and arterio-graphic Epidemiological studies and arterio-graphic

data support HDL benefitdata support HDL benefit Niacin and combination therapy are Niacin and combination therapy are

effective and proven therapy for HDL effective and proven therapy for HDL raisingraising

Apo-A1 targeting appear to be the most Apo-A1 targeting appear to be the most promising strategy to enhance reverse promising strategy to enhance reverse cholesterol transportcholesterol transport

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Don’t forgetDon’t forgetAerobic exerciseAerobic exerciseLSMLSMSmoking cessationSmoking cessationCombination therapyCombination therapy

A specific HDL raising agents may need further 5-10 years to show in the market

Conclusions

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It’s complex:It’s complex:Genes involved in HDL metabolismGenes involved in HDL metabolism

HDL assosciated Apos.:HDL assosciated Apos.: Apo-A1Apo-A1 Apo-EApo-E Apo-IVApo-IV

Modifying plasma enzymes and transfer proteinModifying plasma enzymes and transfer protein LCAT- CETP- PLTPLCAT- CETP- PLTP LPL- HL- Endoth. lipase LPL- HL- Endoth. lipase

Cellular and cell surface proteinCellular and cell surface protein ABC1ABC1 SR-B1SR-B1

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Studies of HDL/apoA-1 Studies of HDL/apoA-1 infusioninfusion

Shah PK. Future Lipidol 2006; 1:55-64.

AgentAgent ModelModel Main effectsMain effects

Recombinant Recombinant apoA-1 MilanoapoA-1 Milano

HumansHumans Stimulation of fecal Stimulation of fecal cholesterol excretioncholesterol excretion

Plasma-derived Plasma-derived human HDL human HDL

HumansHumans Stimulation of reverse Stimulation of reverse cholesterol transportcholesterol transport

Plasma-derived Plasma-derived human HDLhuman HDL

Hyperlipidemic Hyperlipidemic humanshumans

Improved endothelial Improved endothelial functionfunction

Recombinant Recombinant apoA-1 Milano apoA-1 Milano (ETC-216)(ETC-216)

Acute coronary Acute coronary syndrome syndrome patientspatients

Coronary atheroma Coronary atheroma regression in 5 weeksregression in 5 weeks

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