1 / 25

The future of HDL raising

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.

arleen
Download Presentation

The future of HDL raising

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

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

  3. 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.

  4. 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.

  5. BP increase In 1.6% 1.6%++BP -------------------- 9 Ashraf Reda,M.D.

  6. Mortality increase 10 Ashraf Reda,M.D.

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

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

  9. 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

  10. 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.

  11. 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.

  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 11 Ashraf Reda,M.D.

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

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

  15. 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. 16 Ashraf Reda,M.D.

  17. 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.

  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 18 Ashraf Reda,M.D.

  19. 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.

  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 20 Ashraf Reda,M.D.

  21. Thank you 22 Ashraf Reda,M.D.

  22. CardioLipid 2007 14-16 November www.lipiday.com

  23. 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.

  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 13 Ashraf Reda,M.D.

  25. Studies of HDL/apoA-1 infusion 17 Shah PK. Future Lipidol 2006; 1:55-64. Ashraf Reda,M.D.

More Related