Transcript Vascular Inflammation in CV Disease: Focus on Lp-PLA2

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
Is Very Low LDL the Answer to Better Prevention?
Relationship between LDL-C and CV Event Rate
30
- Primary prevention
4S - Pl
- Secondary prevention
25
Rx - Statin therapy
Event rate (%)
Pl - Placebo
20
4S - Rx
LIPID - Pl
15
LIPID - Rx
10
CARE - Rx
PROSPER - Rx
HPS - Rx
ALLHAT - Rx
5
ASCOT - Rx
0
70 (1.8)
90 (2.3)
CARE - Pl
PROSPER - Pl
HPS - Pl
WOSCOPS - Rx
AFCAPS/TexCAPS - Pl
AFCAPS/TexCAPS
- Rx
110 (2.8)
WOSCOPS - Pl
ALLHAT - Pl
ASCOT - Pl
130 (3.4)
150 (3.9)
170 (4.4)
190 (5.0)
210 (5.4)
LDL-C achieved mg/dL (mmol/L)
Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q.
NCEP ATP III: LDL
-C Goals
LDL-C
(2004 proposed modifications)
190 -
High Risk
Moderately
High Risk
Moderate
Risk
Lower
Risk
CHD or CHD risk
equivalents
≥ 2 risk
factors
≥ 2 risk
factors
< 2 risk
factors
(10-yr risk
>20%)
(10-yr risk
10-20%)
(10-yr risk
<10%)
goal
160
LDL-C level
mg/dL
160 -
goal
goal
mg/dL
mg/dL
130
130 -
goal
100
mg/dL
130
or
optional
100
mg/dL*
100 -
or
optional
70
mg/dL*
Existing LDL-C goals
Proposed LDL-C goals
70 *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
Grundy SM et al. Circulation 2004;110:227-239.
IS LDL CHOLESTEROL
THE “ONLY” PLAYER IN
ATHEROSCLEROSIS?
Stages of Atherosclerosis
LUMEN
LDL
INTIMA
MEDIA
Stages of Atherosclerosis
LUMEN
Adhesion
molecules
Oxidized LDL
Lp-PLA2
INTIMA
Lyso-PC
OxFA
MEDIA
Stages of Atherosclerosis
LUMEN
Monocytes
Cytokines
Adhesion
molecules
Plaque
formation
Oxidized LDL
Lp-PLA2
Foam cell
INTIMA
Macrophage
Lyso-PC
OxFA
MEDIA
Stages of Atherosclerosis
LUMEN
LDL
Monocytes
Cytokines
Adhesion
molecules
Plaque
formation
Oxidized LDL
Lp-PLA2
Foam cell
INTIMA
Macrophage
Lyso-PC
OxFA
MEDIA
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
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
20+ years of studies:
Patients with smaller LDL size have greater
CHD risk at any given level of LDL-C.
Lower risk
Higher risk
130 mg/dL
130 mg/dL
Large LDL
(Pattern A)
Small LDL
(Pattern B)
LDL
Cholesterol
Balance
But they also
have more
particles!
Similar LDL Levels Do NOT Mean Similar Risk
LDL = 66
LDL = 81
Phenotype B
Phenotype A
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
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
The Quebec Cardiovascular Study: Risk Factors for IHD
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
Type 2 DM
4.4%
14.8%
5.7 + 1.0
6.1 + 1.1
1.04 + 0.2
0.96 + 0.24
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
Cholesterol,
mmol/L
HDL, mmol/L
< 0.001
0.003
<0.001
0.002
0.01
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
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)
LDL particle number and risk of future
cardiovascular disease in the Framingham
Offspring Study (J Clin Lipidol 2007;1:583-92)
Stages of Atherosclerosis
LUMEN
Monocytes
Cytokines
Adhesion
molecules
Plaque
formation
Lp-PLA2
Foam cell
Oxidized LDL
INTIMA
Macrophage
Lyso-PC
OxFA
MEDIA
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
OxLDL, a strong predictor for acute coronary heart
disease events in apparently healthy middle-aged men
from the general population
• Prospective, nested, case-control study
(MONICA/KORA population)
• Men without coronary heart disease (CHD) or
diabetes mellitus at baseline
• Mean follow-up time 5.6 + 2.6 years
• OxLDL was measured in 88 men who developed CHD
and in 258 age-and survey-matched controls
• Hazard ratios (HR) were estimated from conditional
logistic-regression models with matching for age
and survey
Circulation 2005; 112: 651-657
Demographic and clinical characteristics of
CHD patients and controls
CHD
Age
61 + 9
BMI (kg/m2)
29 + 4
HTN
76%
Current smoker
37%
Total cholesterol 257+42
HDL
50+15
TC/HDL ratio
5.5+1.6
LDL
171+39
oxLDL (U/L)
110+32
Controls
61 + 8
28 + 4
56%
22%
243+42
52+15
5+1.8
157+40
93+28
Circulation 2005; 112: 651-657
p
NS
0.049
0.001
0.018
0.012
NS
0.02
0.005
<0.001
oxLDL is better than all other lipid parameters in
prediction of acute CHD after adjustment for various
cardiovascular risk factors
HR for upper vs. lower third
p value
OxLDL
4.25 (2.09-8.63)
0.012
HDL
0.69 (0.37-1.29)
0.074
TC/HDL
2.32 (1.23-4.37)
0.009
LDL
2.38 (1.25-4.52)
0.065
Circulation 2005; 112: 651-657
Improved indentification of patient with CAD by
oxLDL
• 431 healthy men and women vs. 490 patients with
established CAD
• Lipid parameters, oxLDL, Lp-PLA2 were compared in
the 2 groups
• Diagnostic accuracy for CAD was determined by
receiver-operating characteristic curve analysis by
measuring the area under the curve
Johnston et al. Am J Cardiol 2006;97:640-645
oxLDL and oxLDL/HDL ratio are the best
predictors 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, placebocontrolled 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
n = 50
Stenosis > 50% 19 (38%)
Prior MI
18 (36%)
PCI
23 (46%)
CABG
26 (52%)
Diabetes
18 (36%)
Stroke
1 (2%)
PVD
6 (12%)
Placebo
n = 50
23 (46%)
12 (24%)
15 (30%)
21 (42%)
21 (42%)
1 (2%)
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
Age (year)
Male
Smoking
Hyperlipidemia
Hypertension
Fam. Hist. CAD
BMI (kg/m2)
Ezetimibe
n = 50
Placebo
n = 50
64
44
14
47
35
21
27
65
41
12
43
38
14
28
+8
(88%)
(28%)
(94%)
(70%)
(42%)
+3
+ 11
(82%)
(24%)
(86%)
(76%)
(28%)
+4
Concomitant Medications
Aspirin
Clopidogrel
ACE inhb. or ARB
Beta-blockers
CCB
Nitrates
Diuretics
OAD
Insulin
* P = 0.02
Ezetemibe
n = 50
Placebo
n = 50
45 (90%)
11 (22%)
41 (82%)
37 (74%)
8 (16%)
10 (20%)
6 (12%)
15 (30%)
6 (12%)
43 (86%)
11 (22%)
34 (68%)
35 (70%)
18 (36%)*
11 (22%)
6 (12%)
17 (34%)
6 (12%)
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
10% additional
reduction
P < 0.001
20% additional
reduction
Final LDL levels were lower in ezetimibe vs. placebo; p < 0.001
Change in Large, Buoyant LDL
P < 0.001
10% additional
reduction
P < 0.001
24% additional
reduction
Final levels ezetimibe vs. placebo: p = 0.007
Change in Small Dense LDL
P < 0.001
36% additional
reduction
P < 0.001
32% additional
reduction
No difference between ezetimibe and placebo in lowering small
dense LDL
Qualitative Lipid Analysis: Change in Particle Size
Placebo/atorva:
Ezetimibe/atorva
Particle Size in Angstrom
268
270
268
270
p = 0.002
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 qualitative
The 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