Què no et pots perdre dels lípids - schta.cat Matas.pdf · metabolisme . ABCG5/8, NPC1L1 . Relació gen/paper de LDL en metabolisme . ... • Avaluant quantitativament HDL en pacients

Lipidologia 2015

Laia Matas

Hospital de la Santa Creu i Sant Pau

• Genètica/Mesures dels lípids

• Teràpies farmacològiques futures

• Articles relacionats amb discontinuitat de tt

Novel genes in LDL metabolism

• L’heretabilitat dels nivells de LDL colesterol és de 40-50%.

• La primera alteració genètica es va descobrir amb l’alteració del

LDL-receptor en HF.

• Genomic wide Association studies (GWAS) han permès identificar

més de 157 locis associats a alteracions de nivells lipídics en

plasma. (30 amb nivells de LDLque explicarien un 12-15% de les

variacions de LDL )

GWAS/Seqüenciació exoma

• Resumeix les troballes més recents de “Genomic Wide association studies” (GWAS), la seqüenciació de l’exoma de pacients amb hipercolesterolèmia familiar assenyalen nous gens en el metabolisme del colesterol-LDL.

• El loci per ABCT (ATP-binding cassette transporter G5 i G8), Niemann-Pick C1-like protein 1, sortilin-1, ABO grup sanguini glicosiltranferases i d’altres s’associen amb nivells de LDL i malaltia coronària.

• La descoberta de nous gens mitjançant el GWAS permetrà millorar la comprensió dels mecanismes metabòlics de les LDL i identificar noves dianes terapèutiques.

GWAS/Seqüenciació exoma

• En pacients amb hipercolesterolèmia familiar

• En HF homozigota s’ha trobat una variant de la lipasa àcida

lisosomal A

• La LIPA comportaria malaltia autosomica recessiva que acumularia

lípids hepàtics i esplènics i comportaria malaltia coronària precoç.

• Altres nous gens implicats inclourien el gen insulin-induced, patatin-

like fosfolipasa... Aquestes troballes encara han de correlacionar-se

amb estudis funcionals per a confirmar el paper en el LDL-colesterol

metabolisme

ABCG5/8, NPC1L1

Relació gen/paper de LDL en metabolisme

Sachdeva.&et&al.,&American&Heart&Journal&157&(2009)&

50%!of!people!!w h o &h a v e &a &c a r d i o v a s c u l a r &e v e n t &h a v e &n o rm a l &L D L RC &l e v e l s &

Riesgo!cardiovascular!residual

4&

Mora&S.&et&al.,&CirculaI on&119&(2009)&2396R2404&

Fewer&LDL&ParI cles&Lower!Risk!

More&LDL&ParI cles&Higher!Risk!

LDLRC&&&115&mg/dL&&&&&&OK!LDLRP&&&1200&nmol/L&&&&↑!

LDLRC&&&115&mg/dL&&&&OK!LDLRP&&&800&nmol/L&&&OK!

Lipoproteínas,!más!allá!de!la!concentración

6&

Patrón frecuente Trastornos metabólicos

Mallol R. et al., Journal of Lipid Research, 2015

Liposcale lípidos parUculas tamañoVLDL LDL HDL

Test!avanzado!de!lipoproteínas!por!RMN:!Liposcale

Atherosclerosis

• Fàrmacs que augmenten HDL han fracassat en la reducció

de risc cv en pacients DM2

• Avaluant quantitativament HDL en pacients en diferents tts

(fenofibrat vs niacina/laropiprant) no hi ha diferències

significatives.

• Conclusió: niacina o fenofibrat, no reverteixen les anomalies

en HDL en DM2 encara que modifiquen la composició de les

HDL de forma diferent.

IMPROVE-IT

MÈTODES

• N:18.144, SCA 10 dies

• 25%dones, 27%DM

• LDL 50-100/50-125mg/dL

• S40 vs S40+E10

• Objectiu: compost de mort cardiovascular, IAM no fatal, ictus no fatal, àngor inestable rehospitalitzant, revasc.>30d

• Seguiment: 6 anys

RESULTATS

• LDL 53.7 vs 69.5 (p<0.001)

• KM objectiu primari 32.7% S40E10 vs 34.7% S40.

• Events adversos similars en ambdos grups

• Subgrup de DM.

IMPROVE-IT

• Afegir ezetimibe a una estatina redueix 24% la LDL amb gran seguretat i escassos AE.

• Redueix risc cv amb corba que inicia separació a partir de l’any de la randomització

• NNT 50, nivells de partida de LDL baixos.

• 48% abandonaments (simva 80, llarg seguiment, càncer...)

• La reducció d’events és consistent amb la previsible amb estatines a igual reducció.

ODYSSEY LONG TERM

• N:2341 alt risc cardiovascular,

LDL>70 + tt amb estatines

• Alirocumab 150mg/14d vs

placebo 2:1.

• Objectiu primari: LDL

24setmanes.

• DURADA 78 SETMANES

• LDL 62% (p<0.001)

• Aliro/LDL 48mg/dL (80%<70)

• Placebo/LDL 119mg/dL (8%)

• Efecte mantingut (52%)

• Discontinuaren 28 vs 25%

• EAs: locals, 5.9 vs 4.2%

• Mialgia 5.4% vs 2.9%

• Neurocognitius 1.2% vs 0.5%

• Oftalmològics 2.9 vs 1.9%

• Anàlisi post-hoc: descens

d’events majors cv 1.7 vs 3.3%

(HR 0.52) p0.02.

ODYSSEY LONG TERM

• El descens de LDL fou clarament significatiu novament amb tt

no estatínic

• Els efectes adversos no van relacionar-se amb nivells de LDL

més baixos

• Altres paràmetres lipídics com lp(a) i triglicèrids i

apolipoproteïna B també van reduir-se.

Aliro Pcbo

Safety and efficacy of evolocumab

• N: 4465

• Aleatoritzats 2:1

• Evolocumab 140/set. o

240/mes, vs placebo

• Seguiment 11mesos

• LDL 61%

• Mantingut

• 73% <70mg/dL vs 3.8%.

Articles

1474 www.thelancet.com Vol 386 October 10, 2015

We assessed the safety, pharmacokinetics, and

pharmacological eff ects of ISIS-APO(a)Rx in healthy

volunteers.

MethodsStudy design and participantsThis randomised, placebo-controlled, double-blind,

phase 1 study was done at the PAREXEL Clinical

Pharmacology Research Unit (Harrow, Middlesex, UK).

We tested ascending doses of ISIS-APO(a)Rx in healthy

adults, aged 18–65 years, with body-mass index (BMI)

less than 32∙ 0 kg/m² and Lp(a) concentration of

25 nmol/L (100 mg/L) or more. To be included, women

had to not be pregnant and not lactating and either

surgically sterile (eg, tubal occlusion, hysterectomy,

bilateral salpingectomy, bilateral oophorectomy) or

postmenopausal, whereas men had to be surgically

sterile, abstinent, or, if engaged in sexual relations of

childbearing potential, must have been using an

acceptable contraceptive method during treatment and

for at least 30 days (single-dose groups) or 12 weeks

(multi-dose groups) after the last dose. Further exclusion

Figure 1: Mechanism by which ISIS-APO(a)Rx suppresses apo(a) protein synthesis

A ubiquitous intracellular ribonuclease RNase H1 recognises the RNA:DNA duplex formed when ISIS-APO(a)Rx binds to the complementary apo(a) mRNA sequence

and cleaves the target, thereby reducing apo(a) protein and preventing generation of Lp(a) particles. TG=triglyceride. PL=phospholipid. FC=free cholesterol.

CE=cholesteryl ester. KIV=kringle IV repeats. KV=kringle V repeat. OxPL=oxidizsed phospholipid. apo(a)=apolipoprotein(a). apoB- 100=apolipoprotein B-100.

This fi gure was adapted from Albers JJ et al 10 with permission.

ISIS-APO(a)Rx

Newly synthesised LDL

apo(a)

Mature

Lp(a)

particle

s-s

PLTG

FC

CE

LPA gene apo(a) mRNA

TranscriptionRNase H1

degrades

apo(a) mRNA

No apo(a)

produced

Antisense oligonucleotide

(single stranded, DNA-like)

apo(a)

apoB-100

KIV1

KIV2

KIV3KIV

4

KIV5KIV

6KIV7KIV

8KIV

9KIV

10

KV

OxPLP

apoB-100

apoB-100

KIV1

KIV2

KIV3KIV

4

KIV5KIV

6 KIV7 KIV

8KIV

9KIV

10

KV

OxPL

OxPL

P

Històries negatives i estatines

.....................................................................................................................................................................................

.....................................................................................................................................................................................

CLINICAL RESEARCHPrevention and epidemiology

Negative stat in-related news stories decrease

stat in persistence and increase myocardial

infarction and cardiovascular mortality:

a nationwide prospective cohort study

Sune Fallgaard Nielsen and Børge Grønne Nordestgaard*

Department of Clinical Biochemistry, 54M1, Herlev and Gentofte Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen,

Herlev Ringvej 75, DK-2730 Herlev, Denmark

Received 10 June 2015; revised 22 September 2015; accepted 6 November 2015

A im We tested the hypothesis that statin-related newsstories, cardiovascular disease, diabetes, statin dose, calendar year,

and socio-demographic status are associated with early statin discontinuation. We also examined frequency and con-

sequences of early statin discontinuation.

Met hods

and result s

From the entireDanish population, westudied 674 900 individuals aged 40 or older who were initiated on statin ther-

apy in 1995–2010, and followed them until 31 December 2011. Individuals on statins increased from , 1%in 1995 to

11%in 2010, while early statin discontinuation increased from 6%in 1995 to 18%in 2010. The odds ratios for early

statin discontinuation vs. continued use were 1.09 (95%confidence interval, 1.06–1.12) for negative statin-related

newsstories,1.04 (1.02–1.07) per increasingcalendar year,1.04 (1.02–1.06) per increasingdefined dailydoseof statin,

1.05 (1.03–1.06) for malesex,1.13 (1.11–1.15) for livingincities,1.67 (1.63–1.71) for other ethnicity thanDanish,0.92

(0.90–0.94) for positive statin-related news stories, 0.73 (0.72–0.74) for baseline cardiovascular disease, and 0.91

(0.90–0.93) for baseline diabetes. During follow-up, the hazard ratios for individuals with vs. without early statin dis-

continuation were 1.26 (1.21–1.30) for myocardial infarction and 1.18 (1.14–1.23) for death from cardiovascular

disease.

Conclusion Early statin discontinuation increased with negativestatin-related newsstories, calendar year, statin dose, malesex, liv-

ing in cities, and with other ethnicity than Danish, while the opposite wastrue for positive statin-related newsstories

and for baselinecardiovascular disease and diabetes. Earlystatin discontinuation wasalso associated with increased risk

of myocardial infarction and death from cardiovascular disease.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Statin compliance † Myocardial infarction † Death from cardiovascular disease † Statin-related news stories

Introduct ion

Although statinsareconsideredamongthesafest drugs,1–3initiation

on statin therapy may lead to side effects ranging from very rare

rhabdomyolysis to less rare and milder symptoms of muscle aches

and other forms of discomfort4–9 leading potentially to early dis-

continuation of statin therapy.10Morethan 90%of themilder symp-

tomsoccur duringthefirst 6monthsfrominitiation of statin therapy

or from up-titration of the statin dose.11 Exposure to negative and

positivestatin-relatednewsstoriesduringthisearlyphasemayplaya

role for the patient in the decision to continue or discontinue statin

therapy beyond the first dispense. This may especially be true for

the patient without ahistory of cardiovascular disease or diabetes,

and who previously considered him- or herself to be in good

cardiovascular health. Additionally,asstatin usereacheswidespread

population level use, statinsarebeingprescribed to individualsof di-

verse health and socio-demographic status, individualswho maydif-

fer from the participants recruited into major statin trials.12–19

* Correspondingauthor. Tel: + 45 3868 3297, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].

European Heart Journal

doi:10.1093/eurheartj/ehv641

European Heart Journal Advance Access published December 1, 2015 European Heart Journal Advance Access published December 1, 2015

by

gu

est on D

ecember 1

4, 2

015

http

://eurh

eartj.ox

ford

jou

rnals.o

rg/

Do

wn

load

ed fro

m

.....................................................................................................................................................................................

.....................................................................................................................................................................................


Negative statin-related news stories decrease

statin persistence and increase myocardial







Aim We tested the hypothesis that statin-related newsstories, cardiovascular disease, diabetes, statin dose, calendar year,

and socio-demographic statusare associated with early statin discontinuation. We also examined frequency and con-


Met hods

and result s

From the entireDanish population, westudied 674900 individualsaged 40 or older who were initiated on statin ther-

apy in 1995–2010, and followed them until 31 December 2011. Individualson statins increased from , 1%in 1995 to




1.05(1.03–1.06) for malesex,1.13(1.11–1.15) for livingincities,1.67(1.63–1.71) for other ethnicity thanDanish,0.92




disease.



and for baselinecardiovascular diseaseand diabetes.Earlystatindiscontinuationwasalso associated with increased risk

of myocardial infarction and death from cardiovascular disease.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Statin compliance † Myocardial infarction † Death from cardiovascular disease † Statin-related newsstories

Introduct ion

Althoughstatinsareconsideredamongthesafest drugs,1–3initiation




continuation of statin therapy.10Morethan90%of themilder symp-








cardiovascular health.Additionally,asstatin usereacheswidespread

population level use,statinsarebeingprescribed to individualsof di-

versehealth and socio-demographic status, individualswho maydif-







by

guest o

n D

ecember 1

4, 2

01

5http

://eurh

eartj.ox

ford

journ

als.org

/D

ow

nlo

aded

from

.....................................................................................................................................................................................

.....................................................................................................................................................................................













Met hods

and result s










disease.





Introduct ion






















by

gu

est on D

ecember 1

4, 2

015

http

://eurh

eartj.ox

ford

jou

rnals.o

rg/

Do

wn

load

ed fro

m

.....................................................................................................................................................................................

.....................................................................................................................................................................................













Met hods

and result s










disease.





Introduct ion






















by

guest o

n D

ecember 1

4, 2

01

5http

://eurh

eartj.ox

ford

journ

als.org

/D

ow

nlo

aded

from

.....................................................................................................................................................................................

.....................................................................................................................................................................................













Met hods

and result s










disease.





Introduct ion






















by

gu

est on D

ecember 1

4, 2

015

http

://eurh

eartj.ox

ford

jou

rnals.o

rg/

Do

wn

load

ed fro

m

.....................................................................................................................................................................................

.....................................................................................................................................................................................













Met hods

and result s










disease.





Introduct ion






















by

guest o

n D

ecember 1

4, 2

01

5http

://eurh

eartj.ox

ford

journ

als.org

/D

ow

nlo

aded

from

.....................................................................................................................................................................................

.....................................................................................................................................................................................













Met hods

and result s










disease.





Introduct ion






















by

guest o

n D

ecember 1

4, 2

01

5http

://eurh

eartj.ox

ford

journ

als.org

/D

ow

nlo

aded

from

.....................................................................................................................................................................................

.....................................................................................................................................................................................













Met hods

and result s










disease.





Introduct ion






















by

gu

est on D

ecember 1

4, 2

015

http

://eurh

eartj.ox

ford

jou

rnals.o

rg/

Do

wn

load

ed fro

m

grgrgr

Què no et pots perdre dels lípids - schta.cat Matas.pdf · metabolisme . ABCG5/8, NPC1L1 . Relació gen/paper de LDL en metabolisme . ... • Avaluant quantitativament HDL en pacients

Documents