Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations...

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