beyond ldl cholesterol: reduction of small dense ldl and of oxidized ldl with combined lipid therapy...
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Beyond LDL Cholesterol: Reduction of Small Dense LDL and of
Oxidized LDL With Combined Lipid Therapy
Rabih R. Azar, MD, MSc, FACCAssociate Professor of Medicine
Division of CardiologyHotel Dieu de France
Saint Joseph University
Risk of CAD according to LDL and HDL
Relationship between LDL-C and CV Event Rate
Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q– 12Q.
LDL-C achieved mg/ dL (mmol/ L)
WOSCOPS - Pl
AFCAPS/ TexCAPS - Pl
ASCOT - PlAFCAPS/ TexCAPS- Rx
WOSCOPS - Rx
ASCOT - Rx
ALLHAT - RxALLHAT - Pl
4S - Rx
HPS - Pl
LIPID - Rx
4S - Pl
CARE - Rx
LIPID - Pl
PROSPER - PlCARE - Pl
HPS - Rx
PROSPER - Rx
0
5
10
15
20
25
30
70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4)
Even
t ra
te (
%)
- Secondary prevention
- Primary prevention
Rx - Statin therapy
Pl - Placebo
I s Very Low LDL the Answer to Better Prevention?
NCEP ATP I I I : LDL-C Goals(2004 proposed modifications)
NCEP ATP I I I : LDLNCEP ATP I I I : LDL--C GoalsC Goals(2004 proposed modifications)(2004 proposed modifications)
* Therapeutic option
70 mg/ dL =1.8 mmol/ L; 100 mg/ dL = 2.6 mmol/ L; 130 mg/ dL = 3.4 mmol/ L; 160 mg/ dL = 4.1 mmol/ L
High Risk
CHD or CHD risk equivalents
(10-yr risk >20% )
LD
L-C
level
100 -
160 -
130 -
190 -
Lower Risk
< 2 risk factors
Moderately High Risk
≥ 2 risk factors
(10-yr risk 10-20% )
goal
160mg/ dL
goal
130mg/ dL
70 -
goal
100 mg/ dL
or optional
70 mg/ dL*
Moderate Risk
≥ 2 risk factors
(10-yr risk <10% )
goal
130 mg/ dL
or optional
100 mg/ dL*
Grundy SM et al. Circulation 2004;110:227-239.
Existing LDL-C goals
Proposed LDL-C goals
IS LDL CHOLESTEROL THE “ONLY” PLAYER IN
ATHEROSCLEROSIS?
LUMEN
MEDIA
INTIMA
Stages of Atherosclerosis
LDL
LUMEN
MEDIA
INTIMA
Oxidized LDL
Adhesion molecules
Lyso-PCOxFA
Lp-PLA2
Stages of Atherosclerosis
CytokinesPlaque formation
Foam cell
Monocytes
Macrophage
Stages of AtherosclerosisLUMEN
MEDIA
INTIMA
Oxidized LDL
Adhesion molecules
Lyso-PCOxFA
Lp-PLA2
CytokinesPlaque formation
Foam cell
Monocytes
Macrophage
Stages of AtherosclerosisLUMEN
MEDIA
INTIMA
Oxidized LDL
Adhesion molecules
Lyso-PCOxFA
Lp-PLA2
LDL
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
150 200
No CHD
Total cholesterol (mg/dL)250 300
CHD
20+ years of studies:Patients with smaller LDL size have greater
CHD risk at any given level of LDL-C.
LDLCholesterol
Balance
130 mg/dL 130 mg/dL
Large LDL(Pattern A)
Small LDL(Pattern B)
Higher riskLower risk
But they also have more particles!
Similar LDL Levels Do NOT Mean Similar Risk
LDL = 66
Phenotype B
LDL = 81
Phenotype A
Small Dense LDLSmall 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
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
Variable IHD free IHD Cases p
Age 56.3 + 6.9 59.3 + 7.7 <0.001
BMI 26.1 + 3.7 26.8 + 4.1 0.07
Systolic BP 130 + 17 137 + 18 < 0.001
Type 2 DM 4.4% 14.8% 0.003
Cholesterol, mmol/L
5.7 + 1.0 6.1 + 1.1 <0.001
HDL, mmol/L 1.04 + 0.2 0.96 + 0.24 0.002
Cholesterol/HDL ratio
5.8 + 1.7 6.7 + 1.9 < 0.001
TG, mmol/L 1.7 + 0.7 2.0 + 0.7 < 0.001
Apo B, mg/L 116 + 30 130 + 32 < 0.001
Lp(a), mg/dL 328 + 347 419 + 471 0.01
The Quebec Cardiovascular Study: Risk Factors for IHD
Small Dense LDL (<255Å) is the Best Predictor of Small Dense LDL (<255Å) is the Best Predictor of Ishemic Heart Disease (IHD) in a Multivariate Ishemic Heart Disease (IHD) in a Multivariate
ModelModel
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
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)
LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study (J Clin Lipidol 2007;1:583-92)
CytokinesPlaque formation
Foam cell
Monocytes
Macrophage
Stages of AtherosclerosisLUMEN
MEDIA
INTIMAOxidized LDL
Adhesion molecules
Lyso-PCOxFA
Lp-PLA2
Pro-atherogenic effects of oxidized LDLPro-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
OxLDLOxLDL, a strong predictor for acute coronary heart , a strong predictor for acute coronary heart disease events in apparently healthy middledisease events in apparently healthy middle--aged men aged men
from the general populationfrom the general population
•• Prospective, nested, caseProspective, nested, case--control study control study (MONICA/KORA population)(MONICA/KORA population)
•• Men without coronary heart disease (CHD) or Men without coronary heart disease (CHD) or diabetes mellitus at baselinediabetes mellitus at baseline
•• Mean followMean follow--up time 5.6 up time 5.6 ++ 2.6 years2.6 years
•• OxLDLOxLDL was measured in 88 men who developed CHD was measured in 88 men who developed CHD and in 258 ageand in 258 age--and surveyand survey--matched controlsmatched controls
•• Hazard ratios (HR) were estimated from conditional Hazard ratios (HR) were estimated from conditional logisticlogistic--regression models with matching for age regression models with matching for age and surveyand survey
Circulation 2005; 112: 651-657
Demographic and clinical characteristics of Demographic and clinical characteristics of CHD patients and controlsCHD patients and controls
CHDCHD ControlsControls ppAgeAge 61 61 ++ 99 61 61 ++ 88 NSNSBMI (kg/mBMI (kg/m22)) 29 29 ++ 44 28 28 ++ 44 0.0490.049HTNHTN 76%76% 56%56% 0.0010.001Current smokerCurrent smoker 37%37% 22%22% 0.0180.018Total cholesterolTotal cholesterol 257257++4242 243243++4242 0.0120.012HDLHDL 5050++1515 5252++1515 NSNSTC/HDL ratioTC/HDL ratio 5.55.5++1.61.6 55++1.81.8 0.020.02LDLLDL 171171++3939 157157++4040 0.0050.005oxLDLoxLDL (U/L)(U/L) 110110++3232 9393++2828 <0.001<0.001
Circulation 2005; 112: 651-657
oxLDLoxLDL is better than all other lipid parameters in is better than all other lipid parameters in prediction of acute CHD after adjustment for various prediction of acute CHD after adjustment for various
cardiovascular risk factorscardiovascular risk factors
HR for upper vs. lower thirdHR for upper vs. lower third p valuep value
OxLDLOxLDL 4.25 (2.094.25 (2.09--8.63)8.63) 0.0120.012
HDL HDL 0.69 (0.370.69 (0.37--1.29)1.29) 0.0740.074
TC/HDLTC/HDL 2.32 (1.232.32 (1.23--4.37)4.37) 0.0090.009
LDLLDL 2.38 (1.252.38 (1.25--4.52)4.52) 0.0650.065
Circulation 2005; 112: 651-657
Improved Improved indentificationindentification of patient with CAD by of patient with CAD by oxLDLoxLDL
•• 431 healthy men and women vs. 490 patients with 431 healthy men and women vs. 490 patients with established CADestablished CAD
•• Lipid parameters, Lipid parameters, oxLDLoxLDL, Lp, Lp--PLA2 were compared in PLA2 were compared in the 2 groupsthe 2 groups
•• Diagnostic accuracy for CAD was determined by Diagnostic accuracy for CAD was determined by receiverreceiver--operating characteristic curve analysis by operating characteristic curve analysis by measuring the area under the curvemeasuring the area under the curve
Johnston et al. Am J Cardiol 2006;97:640-645
oxLDLoxLDL and and oxLDLoxLDL/HDL ratio are the best /HDL ratio are the best predictors of CADpredictors of CAD
Johnston et al. Am J Cardiol 2006;97:640-645
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
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
OBJECTIVE
TO EVALUATE THE EFFECT OF ATORVASTATIN 40 mg and of
ATORVASTATIN 40 mg + EZETIMIBE ON OX-LDL CHOLESTEROL
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
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
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
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
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
Inclusion Criteria
Ezetimibe Placebon = 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
Baseline Characteristics
Ezetimibe Placebon = 50 n = 50
Age (year) 64 + 8 65 + 11Male 44 (88%) 41 (82%)Smoking 14 (28%) 12 (24%)Hyperlipidemia 47 (94%) 43 (86%)Hypertension 35 (70%) 38 (76%)Fam. Hist. CAD21 (42%) 14 (28%)BMI (kg/m2) 27 + 3 28 + 4
Concomitant Medications
Ezetemibe Placebon = 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
Statin Use at Baseline
• 90% of patients were using a statin prior to randomization
• Simvastatin 53%
• Atorvastatin 30%
• Fluva or pravastatin 7%
• None 10%
Change in LDL
P < 0.001 P < 0.001
Final LDL levels were lower in ezetimibe vs. placebo; p < 0.001
10% additional reduction
20% additional reduction
Change in Large, Buoyant LDL
P < 0.001 P < 0.001
Final levels ezetimibe vs. placebo: p = 0.007
10% additional reduction
24% additional reduction
Change in Small Dense LDL
P < 0.001 P < 0.001
No difference between ezetimibe and placebo in lowering small dense LDL
36% additional reduction
32% additional reduction
Qualitative Lipid Analysis: Change in Particle Size
Particle Size in AngstromParticle Size in AngstromPlacebo/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
Change in VLDL
P = 0.07 P < 0.001
P = ns P = ns
Correlation Between the Changes in ox-LDL and Total LDL
Safety End-Point
There was no elevation of CPK or SGPT in any patient of the 2
groups
Summary of Results: Effects of Atorvastatin and Ezetimibe on Various
Lipid Parameters
LDL Large LDL
Small dense LDL
Particle size
HDL VLDL Ox-LDL
More potent statin
Ezetimbe
The changes induced by statin are quantitative and The changes induced by statin are quantitative and qualitativequalitativeThe Changes induced by ezetimibe are only quantitativeThe Changes induced by ezetimibe are only quantitative
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