Ληπηδαηκηθές παράκεηροη πέρα ηφλ

θιαζηθώλ: ApoB, ApoA, Lp(a), HPLA2
Γεώργηος Σ. Γθοσκάς MD, PhD, FESC
Αλ. Γηεσζσληής Β Καρδηοιογηθής Κιηληθής,
Δσρφθιηληθή Αζελώλ

ΓΗΛΩΣΗ ΣΥΓΚΡΟΥΣΗΣ ΣΥΜΦΔΡΟΝΤΩΝ

Τα προεγούκελα δύο τρόληα έτφ ιάβεη ηηκεηηθές ακοηβές
φς ζύκβοσιος ή οκηιεηής από ηης αθόιοσζες
θαρκαθεσηηθές εηαηρείες:
SANOFI, MENARINI, GALENICA, ASTRAZENECA,
VIANEX, PFIZER, BAYER

Residual risk after statin treatment in major
intervention trials
Risk reduction (%)

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

Risk of primary event (%)
Kastelein JJP, 2005

December 2005

Apolipoproteins A and B
• From a technical point of view there are advantages in the

determination of apo B and apo A1.
Good immunochemical methods are available and easily run in
conventional autoanalysers. The analytical performance is
good.
The assay does not require fasting conditions and is not
sensitive to moderately high TG levels.

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

―Normal‖ LDL-C Levels in People with DM
or MS Can Be Misleading...
No diabetes

Diabetes

LDL particles

LDL particles

apoB
LDL-C
Small, dense
LDL with
more apoB

“Normal” LDL-C level

“Normal” LDL-C level, however:
Number of LDL particles
Concentration of 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

estimate of HDL concentration.
Each HDL particle may carry several apo A1 molecules.
Plasma apo A1 of 120 mg/dL for men and 140 mg/dL for
women approximately correspond to what is considered as
low for HDL-C.

Apolipoprotein B/apolipoprotein A1 ratio

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

Lp(a) consists of a cholesterol-rich LDL particle
with one molecule of apo B-100
and a molecule of apo(a)

Nordestgaard B G et al. Eur Heart J 2010;eurheartj.ehq386

Lp(a) and pathogenesis of vascular disease
 via prothrombotic/anti-fibrinolytic effects as
apolipoprotein(a) possesses structural homology with
plasminogen and plasmin but has no fibrinolytic activity
and
 via accelerated atherogenesis as a result of intimal deposition
of Lp(a) cholesterol

Typical distributions of lipoprotein(a) levels
in the general population
N~3000

N~3000

About 20% of people are thought to have plasma Lp(a) levels
over 50 mg/dL
Nordestgaard B G et al. Eur Heart J 2010;eurheartj.ehq386

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.

Determinants of Lp (a) levels
• wide variability between individuals but stable within





individuals
12% higher in women than men

Physical exercise and diet do not have any impact
affected by hormones, liver & renal failure
Alcohol consumption might lower Lp (a)

Mainly determined genetically depending on Apo (a) genotype
Apo (a) genotype distributions vary widely between populations
 Caucasians, Chinese, Japanese – predominantly low levels

 Hispanics – intermediate levels
 Africans – higher levels

Elevated Lp(a) Levels In Patients with
Hypothyroidism

Elevated lipoprotein(a) levels are
associated with an increased risk of
CAD development and MI
occurrence

Patients with mild thyroid failure
have higher lipoprotein(a) levels,
which increases their risk of CAD

P<.005

Lipoprotein(a) Levels,
U/L

300
250
200
150
100
50
0

Patients With
Mild Thyroid Control Group*
Failure

PROCAM. Lipoprotein(a) and cardiovascular risk.
Kung AW, et al. Clin Endocrinol. 1995;43:445-449.

Lipoprotein(a), LDL Levels
and Cardiovascular Disease

Suk Danik, J. et al. JAMA 2006;296:1363-1370

Risk ratio and 95% CI (log scale)

Risk ratios of coronary heart disease by
quantiles of usual lipoprotein(a) levels.

(A) Adjustment for age and sex only.

Usual Lp(a) (mg/dl)
Geometric mean (log scale)

(B) Further adjustment for systolic blood pressure, smoking status, history of diabetes, body mass
index, and total cholesterol.

Nordestgaard B G et al. Eur Heart J 2010

Lp (a): Consensus Paper by the European
Atherosclerosis Society

Lp (a) and CVD risk

 Elevated Lp(a) levels associate robustly and specifically
with increased CVD risk.
 The association is continuous in shape without a threshold
and does not depend on high levels of LDL or non-HDL
cholesterol, or on the levels or presence of other
cardiovascular risk factors

Nordestgaard B G et al. Eur Heart J 2010

Recommendations: Lp(a) measurement
Lp(a) should be measured once in all subjects at intermediate or
high risk of CVD/CHD
•≥3% 10-year risk of fatal CVD according to the European
guidelines
•≥10% 10-year risk of fatal and/or non-fatal CHD according to
the US guidelines




who present with
premature CVD
familial hypercholesterolemia
a family history of premature CVD and/or elevated Lp(a)
recurrent CVD despite statin treatment

Nordestgaard B G et al. Eur Heart J 2010

Desirable levels for LDL-cholesterol and Lp(a)
levels in the fasting or non-fasting state

Nordestgaard B G et al. Eur Heart J 2010

Modification of Lp(a) levels

• Lp(a) is relatively refractory to both lifestyle and drug
intervention

• Statins consistently and modestly decrease elevated Lp(a) in
patients with heterozygous familial hypercholesterolaemia

Effect of Niacin on Lp(a) levels
• Niacin reduces Lp(a) levels by up to 30–40% in a dose-

dependent manner [1-3g/d]
In addition, exerts other potential beneficial effects by
-

 LDL cholesterol
 Total cholesterol
 Triglycerides
 Remnant cholesterol
 HDL cholesterol

Chapman MJ et al. Pharmacol Ther 2010;126:314-45

Other potent therapies for lowering Lp(a)





Inhibitors of CETP (anacetrapib)
Antisense oligonucleotides (mipomersen)
Thyroid hormone analogue therapies
LDL-apheresis
PCSK6

Lp-PLA2 is highly expressed in carotid plaques

Atik B, et al. PLoS ONE 2010; 5: e11026

The role of Lp-PLA2 in Atherosclerosis
LUMEN

Oxidized LDL

INTIMA

MEDIA

The role of Lp-PLA2 in Atherosclerosis
LUMEN

Adhesion
molecules
Oxidized LDL
Lp-PLA2

INTIMA
Lyso-PC
OxFA

MEDIA

The role of Lp-PLA2 in Atherosclerosis
LUMEN

Monocytes
Cytokines
Adhesion
molecules

Plaque
formation

Oxidized LDL
Lp-PLA2

Foam cell
INTIMA

Macrophage
Lyso-PC
OxFA

MEDIA

Contrasting histopathologic characteristics of a
stable versus ruptured plaque

Stable plaque
Low Lp-PLA2 content

Ruptured plaque
High Lp-PLA2 content
Corson MA, et al. Am J Cardiol 2008;101[suppl]:41F–50F

2000

Circulation, 2004

Circulation, 2004

Circulation, 2006

JACC, 2008

Tsimikas S, et al. European Heart Journal (2009) 30, 107–115

Elevated Lp-PLA2 is consistently associated
with a doubling of risk for CVD

ARIC Study: Lp-PLA2 Increases Risk of Ischemic Stroke at All
Levels of Blood Pressure

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

Tertile of Systolic Blood Pressure
*p=0.03, **p< 0.005, ¶p<0.0001 vs. Lp-PLA2 below median

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.

Gorelick et al. Am J Cardiol Supplement 2008

P A F -A Hactivity
a c tiv ity
(n m o l/m l/m in )
(nmol/ml/min)
Lp-PLA2

Τα επίπεδα ηες Lp-PLA2 ζσζτεηίδοληαη κε ασηά ηφλ 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

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 )

Mean LDL particle size (A)

Gazi I, et al. Clinical Chemistry 2005; 51:2264-2273

High Lp-PLA2 Activity Adds to CV Risk Associated with the
Metabolic Syndrome in the Malmö Study

Αζζελείς σπουήθηοη γηα κέηρεζε Lp-PLA2
1. Άηοκα κέζοσ θηλδύλοσ κε 2 παράγοληες θηλδύλοσ, ή
κεηαβοιηθό ζύλδροκο ή έλαλ κόλο παράγοληα θηλδύλοσ, όπφς
ηο θάπληζκα ή ειηθία > 65
2. Υυειού θηλδύλοσ αζζελείς ζε ζεραπεία γηα λα ερεσλεζεί αλ
ε πιάθα ηοσς παρακέλεη εσάιφηε
3. Σηε περίπηφζε ορηαθώλ επηπέδφλ ιηπηδίφλ, πτ κε LDL 131 ή
HDL 39

4. Σηε περίπηφζε σγηώλ αηόκφλ κε ορηαθή σπέρηαζε. Ο
θίλδσλος γηα εγθεθαιηθό κπορεί λα είλαη 3.5 - 6.8 θορές
κεγαιύηερος από ηολ θίλδσλο ποσ δηαηρέτοσλ όζοη έτοσλ
τακειή πίεζε θαη τακειή Lp-PLA2

Τα σποιηπηδαηκηθά θάρκαθα κεηώλοσλ ηα επίπεδα ηες Lp-PLA2
ζηο πιάζκα

Percent reduction in 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.

Darapladib (Specific Lp-PLA2 inhibitor)
reduces Lp-PLA2 activity in plasma

Mohler ER et al, JACC 2008; 51: 1632-1641

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
Darapladib—Thrombolysis 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.