Presentation is loading. Please wait.

Presentation is loading. Please wait.

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.

Similar presentations


Presentation on theme: "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."— Presentation transcript:

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

4

5 IS LDL CHOLESTEROL THE “ONLY” PLAYER IN ATHEROSCLEROSIS?

6 LUMEN MEDIA INTIMA Stages of Atherosclerosis LDL

7 LUMEN MEDIA INTIMA Oxidized LDL Adhesion molecules Lyso-PC OxFA Lp-PLA 2 Stages of Atherosclerosis

8 Cytokines Plaque formation Foam cell Monocytes Macrophage Stages of Atherosclerosis LUMEN MEDIA INTIMA Oxidized LDL Adhesion molecules Lyso-PC OxFA Lp-PLA 2

9 Cytokines Plaque formation Foam cell Monocytes Macrophage Stages of Atherosclerosis LUMEN MEDIA INTIMA Oxidized LDL Adhesion molecules Lyso-PC OxFA Lp-PLA 2 LDL

10 Risk of CAD according to LDL and HDL

11 Cholesterol distribution in CHD and non-CHD populations 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 35% of CHD occurs in people with TC considered optimal (<200mg/dL) Adapted from Castelli W. Atherosclerosis 1996 Framingham Heart Study — 26-year follow-up No CHD Total cholesterol (mg/dL) CHD

12 1 major risk factor 0 major risk factors 2 major risk factors 3 major risk factors 4 major risk factors 62.4% 0 to 1 major risk factor N=87,869 4 Major modifiable risk factors: hypertension, smoking, hypercholesterolemia, diabetes Traditional risk factors are a useful first step in determining who could be at risk for a coronary event Exposure to one or more CHD risk factors is also highly prevalent in individuals who do not develop clinical CHD Less than 10% of patients have 3 or 4 major risk factors Secondary testing can be used to further stratify individuals for CHD risk Prevalence of major risk factors in men with CHD Khot, et al. JAMA. 2003

13

14

15

16

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

18 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, 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

19 Mechanism of Increased Atherogenicity Direct Mechanisms: –Enhanced oxidative susceptibility –Reduced clearance by LDL receptors in the liver with increased LDL receptor-independent binding in the arterial wall –Endothelial dysfunction Indirect Mechanisms: –Inverse relationship with HDL-C –Marker for accumulation of atherogenic triglyceride remnant particles –Insulin resistance

20

21 Inverse Relationship Between Small Dense LDL and HDL-C

22 The “Good” and “Bad” LDL Large LDL subclasses 1 and 2 are the “good or normal” LDL that are responsible for the transport of cholesterol throughout the body Small LDL subclasses 3 through 7 are “bad or abnormal” that are easily oxidized and promote cardiovascular disease

23 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

24 VariableIHD freeIHD Casesp Age <0.001 BMI Systolic BP < Type 2 DM4.4%14.8%0.003 Cholesterol, mmol/L <0.001 HDL, mmol/L Cholesterol/HDL ratio < TG, mmol/L < Apo B, mg/L < Lp(a), mg/dL The Quebec Cardiovascular Study: Risk Factors for IHD

25 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

26 The Quebec Cardiovascular Study RESULTS: 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)

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

28

29

30 Cytokines Plaque formation Foam cell Monocytes Macrophage Stages of Atherosclerosis LUMEN MEDIA INTIMA Oxidized LDL Adhesion molecules Lyso-PC OxFA Lp-PLA 2

31

32

33 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

34

35

36

37

38

39

40

41 Low risk 35%Intermediate risk 40%High risk 25% No major risk factors and low Framingham risk score At least one major risk factor or family history Established CHD or CHD risk equivalent 5-year follow up Intensive risk intervention Further testing required to determine appropriate clinical direction Initial risk assessment and physical examination Refining cardiac risk assessment in asymptomatic patients Greenland P, et al. Circ CRP; Lp-PLA2; Small dense LDL; Ox LDL

42 Effect of Ezetimibe/Atorvastatin Combination on Oxidized LDL-Cholesterol in Patients With CAD or CAD Equivallent Rabih Azar, Georges Badaoui, Antoine Sarkis, Mireille Azar, Hermine Aydanian, 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 Coll Cardiol March 2010 (abstract) In press: Am J Cardiol July 2010 (manuscript) Sponsored by Pharmaline

43 RATIONAL Ox-LDL is a more potent predictor of cardiovascular risk than standard lipid parameters The majority of clinical trials have tested the efficacy of lipid lowering therapy against standard lipid parameters Rare trials: statins decrease ox-LDL Ezetimibe allows potent reductions of LDL when added to statin therapy The effect of ezetimibe on ox-LDL has however, never been studied This effect is important to investigate given the controversy surrounding ezetimibe’s use

44 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

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

46 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

47 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 2 Creatinin clearance < 30 mL/min CPK or SGPT > 2 times upper normal

48 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

49 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

50 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

51 Inclusion Criteria EzetimibePlacebon = 50 Stenosis > 50%19 (38%)23 (46%) Prior MI18 (36%)12 (24%) PCI23 (46%)15 (30%) CABG26 (52%)21 (42%) Diabetes18 (36%)21 (42%) Stroke1 (2%)1 (2%) PVD6 (12%)5 (10%) The number of inclusion criteria is superior to 100% because each patient may have more than 1 criterion that defines CAD

52 Baseline Characteristics Ezetimibe Placebon = 50 Age (year) Male44 (88%)41 (82%) Smoking14 (28%)12 (24%) Hyperlipidemia47 (94%)43 (86%) Hypertension35 (70%)38 (76%) Fam. Hist. CAD21 (42%)14 (28%) BMI (kg/m 2 )

53 Concomitant Medications EzetemibePlacebon = 50 Aspirin45 (90%)43 (86%) Clopidogrel 11 (22%)11 (22%) ACE inhb. or ARB41 (82%)34 (68%) Beta-blockers37 (74%)35 (70%) CCB8 (16%)18 (36%)* Nitrates10 (20%)11 (22%) Diuretics6 (12%)6 (12%) OAD15 (30%)17 (34%) Insulin6 (12%)6 (12%) * P = 0.02

54 Statin Use at Baseline 90% of patients were using a statin prior to randomization Simvastatin53% Atorvastatin30% Fluva or pravastatin7% None10%

55 Change in LDL in the Placebo/Atorva group P < Additional 10% reduction in LDL when shifting to atorva 40 mg/day

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

57 Change in Large, Buoyant LDL in the Placebo/Atorva Group P < Additional 10% reduction in LDL when shifting to atorva 40 mg/day

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

59 Change in Small Dense LDL in the Placebo/Atorva Group P < Additional 36% reduction in LDL when shifting to atorva 40 mg/day

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

61 Qualitative Lipid Analysis: Change in Particle Size Particle Size in Angstrom Particle Size in Angstrom Placebo/atorva: p = Ezetimibe/atorva268270p = Prevalence of type A phenotype increased from 62% to 70% in the placebo group and from 58% to 74% in the ezetimibe group

62 Change in VLDL in the Placebo/Atorva Group P = 0.07

63 Change in VLDL P = 0.07 P < 0.001

64 P = ns

65 Change in Ox-LDL p = NS p = 0.02 EZE EZE Placebo

66

67 Correlation Between the Changes in ox-LDL and Total LDL

68 Safety End-Point There was no elevation of CPK or SGPT in any patient of the 2 groups

69 Summary of Results: Change in Different Lipid Parameters Ezetimibe + Atorva Placebo + Atorva p = 0.01 p = p = ns p = 0.05 p = ns p = 0.02 % reduction

70 Summary of Results: Effects of Atorvastatin and Ezetimibe on Various Lipid Parameters LDLLarge LDL Small dense LDL Particle size HDLVLDLOx-LDL More potent statin Ezetimbe The changes induced by statin are quantitative and qualitative The Changes induced by ezetimibe are only quantitative

71 Conclusions Aggressive reduction of LDL is currently recommended for high risk patients Potent statins should be used as first line therapy In our study, increasing the potency of statin therapy by switching to atorvastatin 40mg: Did not affect ox-LDL Resulted in quantitative and qualitative improvement in lipid profile Was extremely safe and well tolerated Ezetimibe in combination with atorvastatin: Significantly decreased ox-LDL Resulted in quantitative improvement in lipid profile Was extremely safe and well tolerated


Download ppt "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."

Similar presentations


Ads by Google