genetic determinants of lipids: concordance and discordance ......loss-of-function pcsk9 mutations...
TRANSCRIPT
Genetic determinants of lipids: concordance and discordance with CV risk
Current Opinion in Lipidology 2011, 22:113–122
LDL Receptor Function and Life Cycle
For illustration purposes only
The Role of PCSK-9 in the Regulation of LDL Receptor
ExpressionFor illustration purposes only
Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low
Prevalence of CHD Events
Adapted from Cohen JC. N Engl J Med 2006;354:1264-72 ARIC=Atherosclerosis Risk in the Community
30
20
10
0
0 50 100 150 200 250 300
No Nonsense Mutation
(N = 3278)
50th
Percentile
Fre
quen
cy
(%)
Mean 138 mg/dL
0 50 100 150 200 250 300
30
20
10
0Plasma LDL Cholesterol in Black
Subjects (mg/dL)
PCSK9142x or PCSK9679X
(N=85) Mean 100 mg/dL(-28%)
9.7%
PCSK9142x or PCSK9679X
No Yes
12
8
4
01.2%
Cor
onar
y H
eart
Dis
ease
(%
)
88% reduction in the risk of CHD events during 15-year follow-up
88%
Male
SBP 150
Col/HDL 5
Smoker
Diabetic
http://qrisk.org
JBS3
Lifetime cardiovascular risk
The lower the better
or
The earlier the better
15 yrs
5 yrs
Impact of Alirocumabon LDL Receptor Expression
66
For illustration purposes only
McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353
8Lancet Published Online October 3, 2013http://dx.doi.org/10.1016/ S0140-6736(13)61914-5
9Lancet Published Online October 3, 2013http://dx.doi.org/10.1016/ S0140-6736(13)61914-5
FACTORES DE RIESGO Y PREVENCIÓN
¿Qué hemos aprendido? • HTA
– Reducción de ictus / IAM
– Independiente del fármaco / Suelo / Efecto J
• Dislipemia– Reduccion ictus / IAM– LDL en la diana ¡¡¡ Estatinas!!!
– HDL?– Otros tratamientos para LDL
CGH 2011
Statin Use and Reduced Cancer-Related Mortality
N Engl J Med 2012; 367:1792-1802
Doy you solemnly
swear to prescribe
statins,
all statins
and nothing but
statins
2013 cholesterol
guidelines
Yes,
I do?
Court
¿hipercolesterolemia o
hipoestatinemia?
Atorvastatin increases expression of NPC1L1 & PCSK9 in hyperlipidemic men
Journal of Lipid ResearchMarch 2011 vol. 52 no. 3 558-565
Estudio SHARP (Study of Heart and Renal Protection )
The effects of lowering LDLcholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of
Heartand Renal Protection): a randomizedplacebo-controlled trial .
Lancet 2011; 377: 2181–92
SHARP: Diseño
Lancet 2011; 377: 2181–92
0 1 2 3 4 5 Años de seguimiento
0
5
10
15
20
25
Por
cent
aje
deev
ento
s(%
)
Ratio de riesgo 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
Placebo
Eze/simv
SHARP: Principales eventos isqu émicos
Lancet 2011; 377: 2181–92