The future of HDL raising

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The future of HDL raising

• By
• Ashraf Reda M.D.
• Minoufiya University
• President of WGLVR

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Peripheral Tissue
Blood Excess cholesterol
Liver
Bile
HDL
Reverse cholesterol transport
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Ashraf Reda,M.D.
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Reverse cholesterol transport and HDL metabolism
Bile
FC
A-1
A-1
CE
CE
FC
ABC1
CE
LCAT
SR-B1
FC
Nascent HDL from liver or intestine
Mature HDL
Macrophage
CE cholesterol ester FC free cholesterol
A-1 apolipoproteinA-1 ABC1 ATP-binding
cassettte protein-1 LCAT Lecithincholesterol
acyl transeferase SR-B1scavenger receptor class
B1
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Ashraf Reda,M.D.
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HDL

• Reverse cholesterol transport(Apo-A1ABC-A1)
• Inhibition of adhesion molecules
• Antioxident
• Vasotonic effect
• Prevent LDL oxidation and deposition

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BP increase In 1.6
1.6BP
--------------------
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Mortality increase
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ILLUMINATE / ILLUSTRATE Torcetrapib increases CV
end points

• Failure of HDL theory????
• Failure of CETP inhibition????

OR
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1 1 1

• HDL interacts with eNOS NO secretion
• Torcetrapib increases BP

There must be a change in HDL function with
Torcetrapib
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Apo-A-1
Apo-B
CE
CE
CETP
Mature HDL
VLDL/LDL
Idea Inhibition of CETP will increase HDL
availability and reduce LDL
Ashraf Reda,M.D.
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Reverse cholesterol transport and HDL metabolism
Bile
FC
A-1
A-1
CE
CE
FC
ABC1
CE
LCAT
SR-B1
FC
Nascent HDL from liver or intestine
Mature HDL
Macrophage
CE cholesterol ester FC free cholesterol
A-1 apolipoproteinA-1 ABC1 ATP-binding
cassettte protein-1 LCAT Lecithincholesterol
acyl transeferase SR-B1scavenger receptor class
B1
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Ashraf Reda,M.D.
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HDL metabolism Reverse cholesterol transport
and the role of CETP
Bile
FC
A-1
A-1
CE
CE
FC
ABC1
FC
LCAT
SR-B1
CE
Nascent HDL from liver or intestine
Mature HDL
Macrophage
CETP
LDL receptor
SR-A
B
Oxidation
CE
VLDL/LDL
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Ashraf Reda,M.D.
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ILLUMINATE / ILLUSTRATEWhy do endpoints
increased with Torcetrapib?

• Interaction with e-NOS lead to BP rise
• Enlarged HDL with impaired interaction with SR-B1
  of the liver
• Induction of Endothelin-1 secretion
• Interfere with the reverse cholesterol transport

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CETP inhibition to raise HDLis it the correct
way to go?

• NO

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There are many way to skin a fish

• We also have many way to raise HDL

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Primary (genetic) causes of low HDL
HDL
A-1

• Apo-A1
• Complete Deficiency
• Mutation (Milano Apo-A1)
• LCAT
• Complete deficiency
• Partial (fish eye disease)
• ABC-1
• Tangier disease (homo- or hetero- zygos)
• Familial hypo alpha lipoproteinemia
• Unknown genetic A/E
• Metabolic syndrome
• FCH with low HDL
• Hypoalphalipoproteinemia

CE
Mature HDL
A-1
FC
ABC-1
FC
Macrophage
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Other therapeutic Approaches

• Milano type-apo A1 acutely increase HDL
• Over expression of LCAT
• ABCA1 activators
• ETC-216 Recombinant Apo-A1 Milano
• ETC-588Phospholipid liposome (Cholesterol
  sponge)
• Liver-X-receptors (LXR) agonists
• Endothelial Lipase inhibitors to prevent Apo-A1
  catabolism

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The current evidence

• Raising HDL is at least as important as reducing
  LDL in reducing coronary events and slowing
  atherosclerosis progression.
• A strong statin Niacin is the most effective
  strategy.
• Meta-analysis showed gt60 RR with combination
  therapy compared with 25 with statin alone

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2009-2011What Are We Waiting For?

• ACCORD Fenofibstatin Vs Statin in 9750 pts with
  DM2
• AIM-HIGH Simva Niacepam Vs Simva in 3300 Pts
  (Metabolic syndrome) with CVD, low HDL and high
  TAG
• Heart Protection Study 2 Treatment of HDL to
  Reduce the Incidence of Vascular Events
  (HPS2-THRIVE)

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Conclusions

• CETP inhibition is a harmful strategy
• Epidemiological studies and arterio-graphic data
  support HDL benefit
• Niacin and combination therapy are effective and
  proven therapy for HDL raising
• Apo-A1 targeting appear to be the most promising
  strategy to enhance reverse cholesterol transport

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Thank you
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CardioLipid 2007 14-16 November www.lipiday.com
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Dont forget
Conclusions
A specific HDL raising agents may need further
5-10 years to show in the market

• Aerobic exercise
• LSM
• Smoking cessation
• Combination therapy

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Its complexGenes involved in HDL metabolism

• HDL assosciated Apos.
• Apo-A1
• Apo-E
• Apo-IV
• Modifying plasma enzymes and transfer protein
• LCAT- CETP- PLTP
• LPL- HL- Endoth. lipase
• Cellular and cell surface protein
• ABC1
• SR-B1

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Studies of HDL/apoA-1 infusion
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Shah PK. Future Lipidol 2006 155-64.
Ashraf Reda,M.D.