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The future of HDL raising By Ashraf Reda M.D. Minoufiya University Minoufiya University President of: WGLVR 1.

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Presentation on theme: "The future of HDL raising By Ashraf Reda M.D. Minoufiya University Minoufiya University President of: WGLVR 1."— Presentation transcript:

1 The future of HDL raising By Ashraf Reda M.D. Minoufiya University Minoufiya University President of: WGLVR 1

2 Bile Reverse cholesterol transport Peripheral Tissue Liver Blood Excess cholesterol HDL: Ashraf Reda,M.D. 6

3 CE FC Macrophage ABC1 Nascent HDL from liver or intestine FC LCAT A-1 Mature HDL CE SR-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 Ashraf Reda,M.D. 7

4 HDL  Reverse cholesterol transport(Apo- A1—ABC-A1)  Inhibition of adhesion molecules  Antioxident  Vasotonic effect  Prevent LDL oxidation and deposition Ashraf Reda,M.D. 2

5 %++BP 9 BP increase In 1.6%

6 Ashraf Reda,M.D. 10 Mortality increase

7 ILLUMINATE / ILLUSTRATE: Torcetrapib increases CV end points  Failure of HDL theory????  Failure of CETP inhibition???? OR Ashraf Reda,M.D. 3

8 1 + 1 = 1  HDL interacts with eNOS & NO secretion  Torcetrapib increases BP + There must be a change in HDL function with Torcetrapib

9 CE Mature HDL Apo-A-1 CE Apo-B VLDL/LDL CETP Idea: Inhibition of CETP will increase HDL availability and reduce LDL Ashraf Reda,M.D. 5

10 CE FC Macrophage ABC1 Nascent HDL from liver or intestine FC LCAT A-1 Mature HDL CE SR-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 Ashraf Reda,M.D. 7

11 CE FC Macrophage ABC1 Nascent HDL from liver or intestine FC A-1 LCAT A-1 Mature HDL CE SR-B1 CE FC Bile VLDL/LDL B CETP CE LDL receptor HDL metabolism: Reverse cholesterol transport and the role of CETP Oxidation SR-A Ashraf Reda,M.D. 8

12 ILLUMINATE / ILLUSTRATE: Why 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 Ashraf Reda,M.D. 11

13 CETP inhibition to raise HDL: is it the correct way to go? NO Ashraf Reda,M.D. 4

14 There are many way to skin a fish We also have many way to raise HDL & Ashraf Reda,M.D. 12

15 Primary (genetic) causes of low HDL  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 HDL A-1 Mature HDL A-1 CE FC ABC-1 Macrophage Ashraf Reda,M.D. 14

16 Ashraf Reda,M.D. 16

17 Other therapeutic Approaches Other therapeutic Approaches  Milano type-apo A1 acutely increase HDL  Over expression of LCAT  ABCA1 activators  ETC-216: Recombinant Apo-A1 Milano  ETC-588:Phospholipid liposome (Cholesterol sponge)  Liver-X-receptors (LXR) agonists  Endothelial Lipase inhibitors to prevent Apo-A1 catabolism Ashraf Reda,M.D. 15

18 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 >60% RR with combination therapy compared with + 25% with statin alone Ashraf Reda,M.D. 18

19 : What Are We Waiting For?  ACCORD: Fenofib+statin 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) Ashraf Reda,M.D. 19

20 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 Ashraf Reda,M.D. 20

21 Ashraf Reda,M.D. 22

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23 Don ’ t forget  Aerobic exercise  LSM  Smoking cessation  Combination therapy A specific HDL raising agents may need further 5-10 years to show in the market Conclusions Ashraf Reda,M.D. 21

24 It ’ s complex: Genes 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 Ashraf Reda,M.D. 13

25 Studies of HDL/apoA-1 infusion Shah PK. Future Lipidol 2006; 1: AgentModel Main effects Recombinant apoA-1 Milano Humans Stimulation of fecal cholesterol excretion Plasma-derived human HDL Humans Stimulation of reverse cholesterol transport Plasma-derived human HDL Hyperlipidemic humans Improved endothelial function Recombinant apoA-1 Milano (ETC-216) Acute coronary syndrome patients Coronary atheroma regression in 5 weeks Ashraf Reda,M.D. 17


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