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Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Division of Cardiology

Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy. Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Division of Cardiology Hotel Dieu de France Saint Joseph University. Risk of CAD according to LDL and HDL.

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Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Division of Cardiology

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  1. Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Division of Cardiology Hotel Dieu de France Saint Joseph University

  2. Risk of CAD according to LDL and HDL

  3. IS LDL CHOLESTEROL THE “ONLY” PLAYER IN ATHEROSCLEROSIS?

  4. Stages of Atherosclerosis LUMEN LDL INTIMA MEDIA

  5. Stages of Atherosclerosis LUMEN Adhesion molecules Oxidized LDL Lp-PLA2 INTIMA Lyso-PC OxFA MEDIA

  6. Stages of Atherosclerosis LUMEN Monocytes Plaque formation Cytokines Adhesion molecules Oxidized LDL Lp-PLA2 Macrophage Foam cell INTIMA Lyso-PC OxFA MEDIA

  7. Stages of Atherosclerosis LUMEN LDL Monocytes Plaque formation Cytokines Adhesion molecules Oxidized LDL Lp-PLA2 Macrophage Foam cell INTIMA Lyso-PC OxFA MEDIA

  8. In spite of major advances made in the screening, detection, and management of heart disease, a major need exists for more accurate ways to predict CV risk Approximately 50% of individuals diagnosed with coronary artery disease do not have high blood cholesterol levels Therefore, other factors must be involved Cholesterol distribution in CHD and non-CHD populations Framingham Heart Study — 26-year follow-up 35% of CHD occurs in people with TC considered optimal (<200mg/dL) No CHD CHD 150 200 250 300 Total cholesterol (mg/dL) Adapted from Castelli W. Atherosclerosis 1996

  9. Similar LDL Levels Do NOT Mean Similar Risk LDL = 66 Phenotype B LDL = 81 Phenotype A

  10. Small Dense LDL • LDL particles are heterogeneous in size, density and composition. Individual can be classified according to their predominant LDL size into: • Phenotype A: large particle size > 26.3 nm in diameter • Phenotype B: Small particle size < 25.8 nm • Phenotype I: Intermediate particle size, 25.8-26.3 nm • LDL phenotype B is in part genetically determined • LDL phenotype B is also influenced by acquired conditions such as: • Obesity • Type 2 DM • Metabolic syndrome

  11. Role of Small Dense LDL in Predicting Ischemic Heart Disease: The Quebec Cardiovascular Study • 2034 men; all initially free of IHD • Followed for 5 years • 108 first IHD recorded • Polyacrylamide gradient gel electrophoresis was used to measure small dense LDL Circulation 2001, 104:2295-9

  12. The Quebec Cardiovascular Study: Risk Factors for IHD

  13. Small Dense LDL (<255Å) is the Best Predictor of Ishemic Heart Disease (IHD) in a Multivariate Model RRs of IHD according to baseline LDL, apoB, and TG and small dense LDL (proportion of small dense LDL above or below median of 39.6%). RR were adjusted for age, BMI, BP, DM, medication use at baseline and family history. Circulation 2001, 104:2295-9

  14. The Quebec Cardiovascular StudyRESULTS: • Among all lipid parameters, small dense LDL (< 255 Å) showed the strongest association with the risk of IHD (RR in men = 4.6; p < 0.001) • This was independent of all nonlipid risk factors and of LDL cholesterol, HDL, TG and Lp(a)

  15. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study (J Clin Lipidol 2007;1:583-92)

  16. Stages of Atherosclerosis LUMEN Monocytes Plaque formation Cytokines Adhesion molecules Lp-PLA2 Macrophage Foam cell Oxidized LDL INTIMA Lyso-PC OxFA MEDIA

  17. Pro-atherogenic effects of oxidized LDL • Oxidized LDL is degraded at a faster rate than native LDL by macrophages leading to lipid accumulation. • Oxidized LDL is chemotactic to monocytes, smooth muscle cells, and T lymphocytes, and induces T-cell activation and monocyte differentiation. • Oxidized LDL inhibits macrophage motility, potentially trapping macrophages in the artery. • Components of oxidized LDL are cytotoxic to cells. • Oxidized LDL inhibits endothelium-dependent relaxation factor. • Oxidized LDL enhances monocyte adhesion to endothelium. • Oxidized LDL induces the expression of monocyte chemotactic protein-1 and granulocyte-macrophage colony stimulating factors. • Oxidized LDL inhibits the migration of endothelial cells. • Oxidized LDL induces the expression of adhesion molecules on the endothelium.Components of oxidized LDL induces interleukin-1 synthesis and secretion by macrophages

  18. Effect of Ezetimibe/Atorvastatin Combination on Oxidized LDL-Cholesterol in Patients With CAD or CAD Equivallent • RabihAzar, Georges Badaoui, Antoine Sarkis, MireilleAzar, HermineAydanian, Serge Harb, Guy Achkouty and Roland Kassab • Will be presented on March 14 at the Meeting of the American College of Cardiology in Atlanta, USA • In press: J Am CollCardiol March 2010 (abstract) • In press: Am J Cardiol July 2010 (manuscript) • Sponsored by Pharmaline

  19. RATIONAL • Ox-LDL and small dense LDL are more potent predictors of cardiovascular risk than standard lipid parameters • The majority of clinical trials have tested the efficacy of lipid lowering therapy against standard lipid parameters • Few studies have shown that statins decrease ox-LDL. The effect of ezetimibe on ox-LDL is however, unknown • This effect is important to investigate given the controversy surrounding ezetimibe’s use

  20. OBJECTIVE TO EVALUATE THE EFFECT OF ATORVASTATIN 40 mg and of ATORVASTATIN 40 mg + EZETIMIBE ON OX-LDL CHOLESTEROL

  21. Effect of Ezetimibe/Atorvastatin Combination on Oxidized LDL-Cholesterol in Patients With CAD or CAD Equivallent • Prospective, randomized, double-blind, placebo-controlled trial • Inclusion criteria: • Patients with CAD • > 50% stenosis on angiography • MI • PCI or CABG • Patients with CAD equivalent • Diabetes requiring medications • Peripheral vascular disease • Stroke • Lipid levels were not entry criteria

  22. Exclusion Criteria • Therapy with a statin more potent than atorvastatin 20 mg/day (atorvastatin 40 or above, rosuvastatin any dose) • Therapy with ezetimibe, any other cholesterol absorption inhibitor, niacine, fibrate within the last 3 months • MI, CABG, PCI within the last 3 months • Age > 80 years • EF < 35% or CHF with NYHA class > 2 • Creatinin clearance < 30 mL/min • CPK or SGPT > 2 times upper normal

  23. Study Protocol • The statin taken by the patient was stopped and replaced by atorvastatin 40 mg/day • Patients were then randomized to ezetimibe 10 mg/day vs. placebo • Duration of treatment 8 weeks

  24. MEASURMENTS • Standard lipid profile (Total cholesterol, VLDL, LDL, HDL) • LDL subfractions: small dense LDL and large buoyant LDL • Mean LDL particle size • Oxidized LDL • CPK, SGPT

  25. End-Points • Primary end-point • Change in ox-LDL • Secondary end-points • Change in small dense LDL • Change in LDL particle size • Safety end-points • Elevation of CPK or SGPT more than twice upper normal

  26. Inclusion Criteria • Ezetimibe Placebo • n = 50 n = 50 • Stenosis > 50% 19 (38%) 23 (46%) • Prior MI 18 (36%) 12 (24%) • PCI 23 (46%) 15 (30%) • CABG 26 (52%) 21 (42%) • Diabetes 18 (36%) 21 (42%) • Stroke 1 (2%) 1 (2%) • PVD 6 (12%) 5 (10%) The number of inclusion criteria is superior to 100% because each patient may have more than 1 criterion that defines CAD

  27. Baseline Characteristics • Ezetimibe Placebo • n = 50 n = 50 • Age (year) 64 + 8 65 + 11 • Male 44 (88%) 41 (82%) • Smoking 14 (28%) 12 (24%) • Hyperlipidemia 47 (94%) 43 (86%) • Hypertension 35 (70%) 38 (76%) • Fam. Hist. CAD 21 (42%) 14 (28%) • BMI (kg/m2) 27 + 3 28 + 4

  28. Concomitant Medications • Ezetemibe Placebo • n = 50 n = 50 • Aspirin 45 (90%) 43 (86%) • Clopidogrel 11 (22%) 11 (22%) • ACE inhb. or ARB 41 (82%) 34 (68%) • Beta-blockers 37 (74%) 35 (70%) • CCB 8 (16%) 18 (36%)* • Nitrates 10 (20%) 11 (22%) • Diuretics 6 (12%) 6 (12%) • OAD 15 (30%) 17 (34%) • Insulin 6 (12%) 6 (12%) * P = 0.02

  29. Statin Use at Baseline • 90% of patients were using a statin prior to randomization • Simvastatin 53% • Atorvastatin 30% • Fluva or pravastatin 7% • None 10%

  30. Change in LDL P < 0.001 P < 0.001 20% additional reduction 10% additional reduction Final LDL levels were lower in ezetimibe vs. placebo; p < 0.001

  31. Change in Large, Buoyant LDL P < 0.001 P < 0.001 10% additional reduction 24% additional reduction Final levels ezetimibe vs. placebo: p = 0.007

  32. Change in Small Dense LDL P < 0.001 P < 0.001 36% additional reduction 32% additional reduction No difference between ezetimibe and placebo in lowering small dense LDL

  33. Qualitative Lipid Analysis: Change in Particle Size Particle Size in Angstrom Placebo/atorva: 268 270 p = 0.002 Ezetimibe/atorva 268 270 p = 0.006 Prevalence of type A phenotype increased from 62% to 70% in the placebo group and from 58% to 74% in the ezetimibe group

  34. Change in VLDL P = 0.07 P < 0.001

  35. P = ns P = ns

  36. Correlation Between the Changes in ox-LDL and Total LDL

  37. Safety End-PointThere was no elevation of CPK or SGPT in any patient of the 2 groups

  38. Summary of Results: Effects of Atorvastatin and Ezetimibe on Various Lipid Parameters The changes induced by statin are quantitative and qualitative The Changes induced by ezetimibe are only quantitative

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