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The future of HDL raising. By Ashraf Reda M.D. Minoufiya University President of: WGLVR. 1. Peripheral Tissue. Blood Excess cholesterol. Liver. Bile. HDL:. Reverse cholesterol transport. 6. Ashraf Reda,M.D . Reverse cholesterol transport and HDL metabolism. Bile. FC. A-1. A-1.
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The future of HDL raising By Ashraf Reda M.D. Minoufiya University President of: WGLVR 1
Peripheral Tissue Blood Excess cholesterol Liver Bile HDL: Reverse cholesterol transport 6 Ashraf Reda,M.D.
Reverse cholesterol transport and HDL metabolism Bile FC A-1 A-1 CE CE FC CE ABC1 LCAT SR-B1 FC Mature HDL Nascent HDL from liver or intestine Macrophage 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 7 Ashraf Reda,M.D.
HDL • Reverse cholesterol transport(Apo-A1—ABC-A1) • Inhibition of adhesion molecules • Antioxident • Vasotonic effect • Prevent LDL oxidation and deposition 2 Ashraf Reda,M.D.
BP increase In 1.6% 1.6%++BP -------------------- 9 Ashraf Reda,M.D.
Mortality increase 10 Ashraf Reda,M.D.
ILLUMINATE / ILLUSTRATE: Torcetrapib increases CV end points • Failure of HDL theory???? • Failure of CETP inhibition???? OR 3 Ashraf Reda,M.D.
1 + 1 = 1 • HDL interacts with eNOS & NO secretion • Torcetrapib increases BP + There must be a change in HDL function with Torcetrapib
Apo-A-1 Apo-B CE CETP CE Mature HDL VLDL/LDL Idea: Inhibition of CETP will increase HDL availability and reduce LDL Ashraf Reda,M.D. 5
Reverse cholesterol transport and HDL metabolism Bile FC A-1 A-1 CE CE FC CE ABC1 LCAT SR-B1 FC Mature HDL Nascent HDL from liver or intestine Macrophage 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 7 Ashraf Reda,M.D.
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 8 Ashraf Reda,M.D.
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 11 Ashraf Reda,M.D.
CETP inhibition to raise HDL:is it the correct way to go? NO 4 Ashraf Reda,M.D.
There are many way to skin a fish & We also have many way to raise HDL 12 Ashraf Reda,M.D.
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 14 Ashraf Reda,M.D.
16 Ashraf Reda,M.D.
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 15 Ashraf Reda,M.D.
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 18 Ashraf Reda,M.D.
2009-2011: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) 19 Ashraf Reda,M.D.
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 20 Ashraf Reda,M.D.
Thank you 22 Ashraf Reda,M.D.
CardioLipid 2007 14-16 November www.lipiday.com
Conclusions A specific HDL raising agents may need further 5-10 years to show in the market Don’t forget Aerobic exercise LSM Smoking cessation Combination therapy 21 Ashraf Reda,M.D.
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 13 Ashraf Reda,M.D.
Studies of HDL/apoA-1 infusion 17 Shah PK. Future Lipidol 2006; 1:55-64. Ashraf Reda,M.D.