Beruflich Dokumente
Kultur Dokumente
:
SANOFI, MENARINI, GALENICA, ASTRAZENECA,
VIANEX, PFIZER, BAYER
Residual risk
36
ASCOT-LLA
64
15
PROSPER
HPS
85
24
WOSCOPS
76
31
69
LIPID
24
76
CARE
24
76
AFCAPS/TexCAPS
37
4S
63
30
CARDS
70
37
0
20
63
40
60
80
100
December 2005
Apolipoproteins A and B
From a technical point of view there are advantages in the
Apolipoprotein B
Apo B is the major apolipoprotein of the atherogenic
lipoprotein families VLDL, IDL, and LDL.
The concentration of apo B is a good estimate of the number
of these particles in plasma.
This might be of special importance in the case of high
concentrations of small dense LDL.
Mixed Hyperlipidemia
Diabetes
LDL particles
LDL particles
apoB
LDL-C
Small, dense
LDL with
more apoB
Lower
Higher
CHD risk
Adapted from Austin MA, Edwards KL Curr Opin Lipidol 1996;7:167-171; Austin MA et al JAMA 1988;260:1917-1921;
Sniderman AD et al Diabetes Care 2002;25:579-582.
Apolipoprotein B
Apo B has been shown in several prospective studies to be
equal to LDL-C in risk prediction.
Apo B has not been evaluated as a primary treatment target
in statin trials, but several post-hoc analyses of statin trials
suggest that apo B may be not only a risk marker but also a
better treatment target than LDL-C.
Apolipoprotein B
major disadvantages
It is not included in algorithms for calculation of global risk
It has not been a pre-defined treatment target in controlled
trials.
Apoliprotein A1
Apo A1 is the major protein of HDL and provides a good
The ratio between apo B and apo A1 has been used in large
prospective studies as an indicator of risk.
INTERHEART study
INTERHEART study
INTERHEART study
N~3000
Lipoprotein(a) levels
Several methods for determination of Lp(a) are available, but
standardization between assays is needed as well as use of
size-insensitive assays.
Lp(a) is generally expressed as total Lp(a) mass; however, it is
recommended to express it as mmol/L (or mg/dL) of Lp(a)
protein.
individuals
12% higher in women than men
P<.005
Lipoprotein(a) Levels,
U/L
300
250
200
150
100
50
0
Patients With
Mild Thyroid Control Group*
Failure
(B) Further adjustment for systolic blood pressure, smoking status, history of diabetes, body mass
index, and total cholesterol.
LDL cholesterol
Total cholesterol
Triglycerides
Remnant cholesterol
HDL cholesterol
Oxidized LDL
INTIMA
MEDIA
Adhesion
molecules
Oxidized LDL
Lp-PLA2
INTIMA
Lyso-PC
OxFA
MEDIA
Monocytes
Cytokines
Adhesion
molecules
Plaque
formation
Oxidized LDL
Lp-PLA2
Foam cell
INTIMA
Macrophage
Lyso-PC
OxFA
MEDIA
Stable plaque
Low Lp-PLA2 content
Ruptured plaque
High Lp-PLA2 content
Corson MA, et al. Am J Cardiol 2008;101[suppl]:41F50F
2000
Circulation, 2004
Circulation, 2004
Circulation, 2006
JACC, 2008
Risk Ratios for Ischemic Stroke Based on Lp-PLA2 Level and SBP
7.0
6.0
6.8
5.0
4.0
3.5 **
3.0
2.3 *
2.0
1.0
0.0
3.5
1.0
< 113 m m H g
2.1
113-130 m m H g
> 130 m m H g
Lp-PLA2 Level:
Hi gh (a bove m e di an)
L ow (bel ow m edi an)
LDLLDL-C in stroke cases 136
LDLLDL-C in matched controls 132
No significant difference.
P A F -A Hactivity
a c tiv ity
(n m o l/m l/m in )
(nmol/ml/min)
Lp-PLA2
Lp-PLA2 sdLDL
r = 0 .3 9 2
p = 0 .0 0 0 1
92
85
79
72
65
59
53
46
40
r=0.36, P<0.001
33
27
-1 0
10
20
30
40
50
60
70
80
90
(nmol/ml/min
Lp-PLA2
P A F - A H activity
a c ti v i ty ( nm
ol /m l /m i n )
s d L D L -C m a s s (m g /d l)
sdLDL-C mass (mg/dl)
92
85
r = - 0 .35
p = 0 .0 00 1
79
72
65
59
53
46
40
33
27
240
r= -0.32, P<0.001
245
250
255
260
265
270
275
280
m e a n L D L p a r tic le s iz e ( A )
Lp-PLA2
1. 2 ,
,
> 65
2.
3. , LDL 131
HDL 39
4. .
3.5 - 6.8
Lp-PLA2
Lp-PLA2
0%
Omega 3FA1
Ezetimibe2
Fenofibrate2,5
Average
Statin2-5
Niacin +
Statin6
Statin
-10%
-20%
-30%
-13%
-18%
-29%
-29%
-40%
-50%
-60%
Tsimihodimos et al, ATVB 2002; 22: 306-311
Tsimihodimos et al, JLR 2003; 44: 927-934
Niacin
Added
To Statin
-53%
Saougos VG, et al. ATVB 2007.
ORIGINAL ARTICLE
Darapladib for Preventing Ischemic Events in Stable
Coronary Heart Disease
The STABILITY Investigators
N Engl J Med 2014; 370:1702-1711
BACKGROUND
Elevated lipoprotein-associated phospholipase A2 activity promotes the development of
vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated
with an increased risk of coronary events. Darapladib is a selective oral inhibitor of
lipoprotein-associated phospholipase A2.
METHODS
In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart
disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary
end point was a composite of cardiovascular death, myocardial infarction, or stroke.
CONCLUSIONS
In patients with stable coronary heart disease, darapladib did not significantly reduce
the risk of the primary composite end point of cardiovascular death, myocardial
infarction, or stroke.
ORIGINAL ARTICLE
Darapladib for Preventing Ischemic Events in Stable
Coronary Heart Disease
The STABILITY Investigators
N Engl J Med 2014; 370:1702-1711
20% of patients stopped the drug because of adverse events, including side effects such
as diarrhea and malodorous feces, urine, and skin. In addition, there was a significantly
increased risk of investigator-reported renal failure in the darapladib-treated patients.
Despite the negative results, GlaxoSmithKline is not yet giving up on darapladib. The
company said it plans to wait for data from the Stabilization of Plaques Using
DarapladibThrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) study
in acute coronary syndrome patients before deciding what to do with the drug's
development. Results of SOLID-TIMI 52 are expected in the first half of 2014.