Lp(a) hyperlipoproteinemia - mightymedic.org · Lp(a) and lipids in relation to inflammation in rheumatoid arthritis. Clin reumatol 2000 High Lp(a) levels in chronic hemodialysis

Lp(a) hyperlipoproteinemia

Rossella Marcucci Malattie Aterotrombotiche

Università degli Studi di Firenze

18 dicembre 2015

Pathways of lipoprotein (a) metabolism

LDL receptor

apo (a)

VLDL LDL Lp(a)

B-100 B-100 B-100

CATABOLISM OF LIPOPROTEIN (a)

Lp(a)

Pregnancy Menopause Hypothyroidism Diabetes End Stage Renal Disease Vascular disease

Lp(a)

Hepatic Cirrhosis HRT Thyroid Hormones

Lp(a) in relation to age and sex Framingham Offspring Study

Men (n=1,284) Women (n=1,394) Age n Lp(a) (mg/dl) n Lp(a) (mg/dl) p* 20-29 34 11.3±12.4 23 10.6±11.7 NS

30-39 245 13.5±14.3 279 12.8±14.6 NS

40-49 432 14.4±17.2 475 15.1±16.0 NS

50-59 360 15.3±17.7 396 17.0±19.3 NS

60-69 189 13.2±17.1 191 16.2±18.6 NS

70+ 11 17.6±18.8 17 16.6±23.0 NS *=difference between men and women

Jenner et al, Circulation 1993

Lp(a) and ACUTE-PHASE reaction

In VITRO: mRNA for Lp(a) is positively regulated by IL-6

is suppressed by TGF-beta1 and TNF-alfa In VIVO:

Lp(a) and lipids in relation to inflammation in rheumatoid arthritis. Clin reumatol 2000 High Lp(a) levels in chronic hemodialysis patients are closely related to the acute-phase reaction. Thromb Haemost 1995 Lp(a) in Behcet’s disease as an indicator of disease activity. Eur J Ophthalmol 2001 Lp(a): an acute-phase reactant? Chem Phys Lipids 1994

Lp(a) and UNSTABLE ANGINA

Admission 7th day 14th day

21th day

Chan

ges

of L

p(a)

lev

els

(%)

100

150

200

250

300

Oshima et al, Ather Thromb 1991

Lipoprotein (a)

ATHERO-THROMBOSIS

APO (a) APO B-100 Cholesterol

LIPOPROTEIN (a): PROATHEROGENIC PROPERTIES

Lipoprotein (a)

ATHERO-THROMBOSIS

APO (a) APO (b)

LIPOPROTEIN (a): PROTHROMBOTIC PROPERTIES

IV IV IV IV IV IV IV IV IV

V

IV IV IV IV IV V p

p IV III II I T S

S

5’

5’ 3’

3’

Plasminogen

Apolipoprotein (a)

8 75-85 91 94 87

IV

Homology: 98-100%

Apo(a) isoforms and Lp(a) levels

IV IV IV IV IV IV IV IV IV

IV

IV IV IV IV IV V p

p IV III II I T S

S

5’

5’ 3’

3’

Plasminogen

Apolipoprotein (a)

IV

Kringle 4: classes 1-10 Each class is present as a single copy, except kringle 4 class 2 that is present in multiple copies (from 3 to 30)

many isoforms of apo(a) (from 300 to 800 KD)

LMW= Higher Lp(a) levels / HMW= Lower Lp(a) levels

J Intern Med 2013

Lp(a) levels in different populations

10 30 50 70

Freq

uenc

y(%)

20

40

60

80 Chinese

10 30 50 70

Freq

uenc

y(%)

20

40

60

80

Europeans

Lp(a) (mg/dl)

90 110 Lp(a) (mg/dl)

10 30 50 70

Freq

uenc

y(%)

20

40

60

80 Africans

90 110 Lp(a) (mg/dl)

CLINICAL STUDIES

Lp(a) and CHD: Meta-analysis

Population-based Nguyen, 1997 Cremer,1994 Ridker, 1993 Schaefer, 1994 Wald, 1994 Alfthan, 1994 Bostom, 1994 Sigurdsson, 1992 Cantin, 1998 Dahlen, 1998 Klausen, 1997 Assman, 1996 Coleman, 1992 Dahlen, 1988

0.5 1 2 4 8 Danesh, Circulation 2000

1.7 (95% CI 1,4-1,9)

Clin Med Cardiol, FI

Associa'onbetweenbaselinelipoprotein(a)levelsandrestenosisa5ercoronarysten'ng:meta-analysisof9cohortstudies(1834

pa:ents)

QinSetal.,Atherosclerosis2013

RibichiniF(1998)

GazzarusoC(2003)

KamitaniT(2005)

LiJX(2008)

YangXZ(2010)

GaoJ(2011)

KhosraviA(2011)

QiDD(2009)

HuJ(2002)

Overall(I-squared=86.9%,p=0.000)

StudiesISR/no-ISRnumber

67/245

87/126

52/121

38/71

36/92

54/113

54/113

166/271

46/82

0.02(-0.25,0.29)

0.11(-0.22,0.43)

0.82(0.41,1.22)

1.11(0.70,1.51)

0.73(0.40,1.07)

0.23(0.03,0.42)

-0.47(-0.84,-0.11)

0.70(0.37,1.03)

0.67(0.39,0.95)

0.42(0.14,0.71)

SMD(95%CI)%

weight

11.66

11.13

10.27

10.27

11.05

12.29

10.72

11.06

11.56

100.00

ISR=in-stentrestenosis;SMD=standardmeandifference

Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke,and Nonvascular Mortality

The Emerging Risk Factors Collaboration: 36 prospective studies, 126,634 subjects

JAMA, 2009

CirculaXon2008

9330subjects10yrsfollow-up498MI

CirculaXon2008

….absolute10-yearriskofMIandIHDincreaseswithincreasingLp(a)levels,Fromwomentomen,andwithsmoking,hypertension,andincreasingage…

TheEmergingRiskFactorCollaboraOon,JAMA2012

TheEmergingRiskFactorCollaboraOon,JAMA2012

Erqou, JACC 2010

Pa'ents Controls pvalue (n=520) (n=520)

Hcy(mmol/L) 12.7(3-95) 10(6-24) 0.001

PAI-1(IU/ml) 16(1-64) 8(4-38) 0.001

Lp(a)(mg/L) 170(1-2141) 135(7-1390)0.02

HeterozygosityforFactorVLeiden20(3.8%) 20(3.8%) ns

HeterozygosityforFactorIIG20210A 21(4.0%) 19(3.6%) ns

HomozygosityforPAI-14G/5G 166(31.9%) 156(30.0%) ns

ThrombophilicriskfactorsinCADpa'ents

Dataaremedianandrangeornumber(%).PAI-1=plasminogenacXvatorinhibitortype1.

Marcuccietal.,Heart2006

1 2 3 4 5 6 7 8 9 10

Independent*riskfactorsforsevere(>70%)caroXdatherosclerosisn=615

aCL

OR(95%CI)*Adjustedforage,sexandtradi'onalriskfactors

5.7(3.1-10.4)

2.88(2.1-3.9)

1.6(1.15-2.2)

7.6(4.9-11.9)

HomozygosityMTHFRC677T

Lp(a)>300mg/L

Homocysteine

FIIpolymorphism

2.8(1.3-5.9)

MarcucciR,etalJThrombHaemost2005

0

50

100

150

200

250

300

Patients (n=280) Controls (n=280)

Lp(a)(mg/L) Lp(a)>300mg/L

207

85

p<0.0001

Lipoprotein(a)andPAD

0%

10%

20%

30%

40%

50%

Patients (n=280) Controls (n=280)

14.3%

39.3%

p<0.0001

ClinMedCardFI

SofietalJVascSurg2005

1 2 3 4 5 6 7 8 9 20

Whole group

aCL

Homocysteine

Factor V

Leiden

OR (95% CI)

*Adjusted for acquired (trauma, surgery, use of oral contraceptives, pregnancy and puerperium, hormone replacement therpay), and thrombophilic risk factors 4.1 (1.4-11.6)

4.4 (2.3-8.3)

8.0 (4.0-15.6)

Clin Med Card FI 2002

Lp(a)>300 mg/L

1.8 (1.2-2.9)

Lp(a) as risk factor for VENOUS thromboembolism

Pts n=603; Ctrl n=430

FII polymorphism

6.7 (3.2-14)

Independent Risk Factors for Idiopathic Venous Thromboembolism

(n=341)

Marcucci et al, AM J Med 2003

* multivariate analysis adjusted for acquired (trauma, surgery, use of oral contraceptives, pregnancy and puerperium, hormone replacement therapy), and thrombophilic risk factors

30% (n=101) pts had no thrombophilic factor Among them 35 (35%) had elevated Lp(a) levels In pts with secondary VTE OR for high Lp(a)

was 1.4 (0.7-1.8) ns

IndependentRiskFactorsforRecurrentVenousThromboembolism

(n=136-23%ofthetotalsample)

Marcucci et al, AM J Med 2003

*Adjusted for acquired (trauma, surgery, use of oral contraceptives, pregnancy and puerperium, hormone replacement therapy), and thrombophilic risk factors

Study OR (95% CI)

Marz et al. 1990

van Wersch et al. 1994

Atsumi et al. 1998

von Depka et al. 2000

Marcucci et al. 2003

0.2 0.5 1 2 5

1.08 (0.64-1.81)

0.30 (0.03-2.51)

4.57 (1.12-18.67)

3.19 (1.93-5.28)

2.05 (1.47-2.86)

1.31 (0.80-2.15)

Total (95% CI)

1.77 (1.14-2.75)

Decreased risk of VTE

Metanalysis of Lp(a) and VTE

Vormittag et al. 2006

Lp(a) > 300 in pts,

n

Lp(a) > 300 in ctrls, n

56/203 30/115

1/31 7/69

13/31 3/22

135/685 19/266

146/603 58/430

72/233 31/122

423/1786 148/1024

Increased risk of VTE

Sofi et al., Am J Med 2007

PHENOTYPE or GENOTYPE?

GENETICEPIDEMIOLOGICSTUDIESANDCAUSALITYLp(a)levelsarepredominantlygene'callydeterminedandnotgreatlyinfluencedbylifestylefactorsandmayvaryupto1000–foldbetweenindividuals.TheLPAgeneonchromosome6codesfortheapo(a)moietyoflipoprotein(a)

PLG (6q26)

LPA (6q26-q27)

GENOME-WIDEHAPLOTYPEASSOCIATIONSTUDYIDENTIFIESTHESLC22A3-LPAL2-LPAGENECLUSTERASARISKLOCUSFORCAD

HaplotypicORforCADassociatedwithCCTCandCTTGhaplotypesderived

fromrs2048327,rs3127599andrs10755578onchromosome6q26-q27

Tregouet et al., Nature Genetics 2009

Clarkeetal.,NEJM2009

48,742 single-nucleoXde polymorphisms (SNPs) in 2,100candidategenes

• 3,145caseswithcoronarydisease• 3,352controls

ReplicaXonwastested in3 independentpopulaXons involving4,486addiXonalcasesand4,594controls

Threechromosomalregion(6–9-1)werestronglyassociatedwiththeriskofcoronarydisease.TheLPAlocuson6q26-27hadthestrongestassociaXon

Clarkeetal.,NEJM2009

Gene'cvariantsassociatedwithLp(a),lipoproteinlevelandcoronarydisease

GENETICEPIDEMIOLOGICSTUDIESANDCAUSALITYLp(a)levelsarepredominantlygene'callydeterminedandnotgreatlyinfluencedbylifestylefactorsandmayvaryupto1000–foldbetweenindividuals.TheLPAgeneonchromosome6codesfortheapo(a)moietyoflipoprotein(a).Varia'oninthisgenehasaprofoundeffectonplasmalevelsofLp(a).Ofpar'cularimportanceistheso-calledKIVtype2sizepolymporphismdefinedbyasequencethatmayoccurbetweentwoandmorethan40-'mesperalleledependentonthespecificgenotype.Thispolymorphismdeterminesthesizeoftheexpressedapo(a)THISMAKESLP(a)ANATTRACTIVETARGETFORAMENDELIANRANDOMIZATIONSTUDY

JInternMed2013

Genetically (KIV 2 repeats) elevated Lipoprotein (a) and increased risk of MI

Kamstrup et al JAMA, 2009

Gene'cally(KIV2repeats)elevatedLipoprotein(a)andincreasedriskofMI

KamstrupetalJAMA,2009

ArangeintotalnumberofKIV-2repeats(suminbothalleles)from6to99.Thenumberofrepeatswasinverselyassociatedwithlp(a)levels

Gene'cally(KIV2repeats)elevatedLipoprotein(a)andincreasedriskofMI

KamstrupetalJAMA,2009

AlownumberofKIV-2repeatswasassociatedwithincreasedriskofMI

JInternMed2013

We invesOgated the KIV-2 repeat and SNPs

(rs1853021, rs1800769, rs3798220, rs10455872)

previouslyassociatedwithLp(a) levels inpaOents

withvenousthrombosis

SOcchietal,manuscriptinpreparaOon

LPAKIV-2repeatinvenousthrombosis(VT)pa'ents

VTpaXents(n=516)

Controls(n=1117) p

KIV-2repeatnumber* 12(5-20) 16(10-26) <0.0001

KIV-2repeatnumberquar:les

Q1

Q2

Q3Q4

191(17.1)193(37.4) <0.0001

*valuesareexpressedasmedian(interquarOlerange)

(≤8repeats),n(%)

(9-14repeats),n(%)

(15-25repeats),n(%)

(≥26repeats),n(%)

327(29.3)118(22.9)

307(27.5)108(20.9)

292(26.1)97(18.8)


1 2 3 4 50

OR(95%CI)

KIV-2repeatquar'les

VTpa'ents,N=516

Controls,N=1117

Q4,n(%)

Q3,n(%)

Q2,n(%)

Q1,n(%) 193(37.4) 191(17.1)

118(22.9) 327(29.3)

108(20.9) 307(27.5)

97(18.8) 292(26.1)

2.99(2.16-4.14)p<0.0001

1.11(0.80-1.55)p=0.526

1.09(0.78-1.54)p=0.606

Associa'onofLPAKIV-2repeatquar'leswithvenousthrombosis(VT)MulOvariatelogisOcregressionanalysis*

*adjustedforage,gender,hypertension,diabetesmellitus,dyslipidemia,smokinghabit,BMI,hyperhomocysteinemia,andhormonaltherapy

Q1:≤8repeats;Q2:9-14repeats;Q3:15-25repeats;Q4:≥26repeats(referencegroup)


1-specificity

sensiXvity

Receiver operating characteristic curve for association with venous thromboembolism

Clinical model is based on nongenetic factors (age, gender, hypertension, diabetes, dyslipidemia, smoking habit, BMI, hyperhomocysteinemia, and hormonal therapy): area under the curve, 0.63 (95% CI, 0.60-0.66).

Genetic model contains LPA KIV-2 repeat number: area under the curve, 0.63 (95% CI, 0.60-0.66).

Combined (genetic + clinical) model contains all clinical and genetic predictors: area under the curve, 0.68 (95% CI, 0.65-0.70).

p=0.980

p=0.0038

p=7.98x10-6


THERAPY

JAMA 1995

DARK bar; minimal LDL reduction (<10%) LIGHTER bar: substancial LDL reduction (>10%)

JAMA 1995

Niacininatherogenicdyslipidemia:Pharmacotherapytoreducecardiovascularrisk(datafrom3doubleblind,placebocontrolledstudies)

ChapmanM.J.,Pharmacology&TherapeuXcs,2010

Dose–responsecurvesfortheefficacyofNiaspan®(ERniacin)inreducingplasmalevelsofTG,LDL-CandLp(a)ontheonehand,andinraisingHDL-Contheother,inpaXentswithdyslipidemia

Extended-ReleaseNiacin(NicoXnicAcid)/Laropiprant

PerryC.M.,Drugs,2009.Efficacyofextended-release(ER)niacin/laropiprantinadultswithprimaryhypercholesterolaemiaor

mixedhyperlipidaemia.

Randomized,double-blind,placebo(PL)-controlled,mulXcentre,24-weektrial.

ERniacin/laropiprant1000mg/20mg(n=800)

*p<0.05,**p<0.001vsPL.

Mipomersen(ISIS301012),asecond-generaXonanXsensetherapytargeXngapolipoproteinB-100.

NatureReviewsDrugDiscovery:7,110-111(February2008)).

Mipomersen,anapolipoproteinBsynthesisinhibitor,forloweringofLDLcholesterolconcentraXonsinpaXentswithhomozygous

familialhypercholesterolaemia:arandomised,double-blind,placebo-controlledtrial

F.J.Raal,etal.Lancet,2010

Mipomersen,anapolipoproteinBsynthesisinhibitor,forloweringofLDLcholesterolconcentraXonsinpaXentswithhomozygous

familialhypercholesterolaemia:arandomised,double-blind,placebo-controlledtrial

F.J.Raal,etal.Lancet,2010

LongitudinalcohortstudyontheeffecXvenessoflipidapheresistreatmenttoreducehighlipoprotein(a)levelsandpreventmajoradversecoronaryevents

JaegerB.R.,NatureClinicalPracXce,2008

PaXenttreatmentcharacterisXcs.PaXentbaselinecharacterisXcs.



P<0,0001

Laboratoryvaluesbeforeandduringapheresistreatment.


Absolutenumbersofmajoradversecoronaryeventsduringlipid-loweringmedicaXonaloneandduringcombinedlipid-loweringmedicaXonandlipidapheresis.




ChangesinannualnonfatalMACEratesbeforeandareriniXaXonoflipidapheresis.

JACC 2011

Eur Heart J 2010

Eur Heart J 2010

ANALYTICAL Sources of variations QUANTIFICATION OF LP(a)

SEMI-quantitative methods: Counterimmunoelettrophoresis

QUANTITATIVE methods: Laurell electrophoresis Nephelometry Turbidimetry RIA ELISA

ANALYTICAL Sources of variations

QUANTIFICATION OF LP(a)

the choice of apo(a) size in the assay calibrator is ARBITRARY and would NOT be representative of all apo(a) sizes in plasma samples the reactivity of the antibodies directed to the repeated antigenic sites of apo(a) K4 type 2 will vary depending on the size of apo(a).

The size variations of apo(a) constitutes a serious challenge for the immunochemical

measurement of Lp(a) in plasma

Eur Heart J 2010

Eur Heart J 2010

Clinicalassessmentincorpora'ngapersonalgenome

EAAshley,etal.,Lancet,May1°,2010

CioniG.1,MarcucciR.1,FaXniC.1,SXcchiE.1,FediS.1,CasolaG.1,TognacciniA.2,AbbateR.1,D'AlessandriG.2

1DiparOmentoAreaCriOcaMedico-Chirurgica,UniversitàdegliStudidiFirenze,Firenze.2SIMT,AziendaOspedalieraUSL3,Pistoia

ACIDONICOTINICO,COLESTEROLOHDLELIPOPROTEINA(a)INUNAPOPOLAZIONEDI

PAZIENTIADALTORISCHIOCARDIOVASCOLARESOTTOPOSTIADAFERESITERAPEUTICA

Valutazionedell'effevodell'acidonicoXnicosulprofilolipidico,inparXcolaresuilivellidicolesteroloHDLedilipoproteina(a),inpazienXsovoposXadaferesi.

Scopodellostudio

Caraperis'chedellapopolazione

PazienX(n°) 8

maschi(n°)femmine(n°)

53

Età(media±DS)anni 64(55-68)

Fumatori,(n°)Sovrappesocorporeo,(n°)BMI(media±DS)

02

23,5±2

Ipertesi(n°)DiabeXci(n°)BroncopneumopaXecronicheostruyve(n°)Malayeautoimmuni(n°)

0000

DurataterapiaafereXca[mediana(min-max)]anni

3,5(2-7)

ipercolesterolemia IIa = 1 pz. iperlipidemiacombinataIIb=1pz.

Diagnosididislipidemiaereditaria:

Prevenzionesecondariaperischemiamiocardicaacuta.malayacoronaricatrivasale=6pz.malayacoronaricapentavasale=1pz.“miseriacoronarica”=1pz.arteriopaXaobliteranteperiferica=8pz.ictusischemico=1pz.aneurismaaortaaddominale=3pz.trombosivenosaprofonda=1pz.

Inassociazionea:Lpa(a)>600mg/lStabilitàclinicadellapopolazioneconfermatada:

assenzadisintomaXcità,ECGariposo,ecocardiogramma,ecostressdasforzoecondobutamina.

Presenzaditrombofiliaereditaria:PolimorfismoG20210Aeterozigote=2pz.FavoreVLeideneterozigote=1pz.

Timing 7-10 giorni

Procedureafere'che

HELP:HEPARININDUCEDLIPOPROTEINPRECIPITATION

DESTRANOSOLFATO

IpazienXsonostaXsovoposXaproceduraafereXcaogni7-10giorni(lineeguidaASFA2010).1,5volumidiplasmatravaXadogniprocedura

TIMING

Sistemi disponibili nella nostra struttura, approvati da FDA (linee guida ASFA 2010)

Nessuneventoavversoregistratonelperiododitrapamento

Disegnodellostudio

Somministrazioneterapiacon

acidonico'nico+laropiprant

T1(basale) T2(3mesi) T3(6mesi)

T1N(basale) T2N(3mesi) T3N(6mesi)* * *

* * *

1°mese(1000mg+20mg)/giorno

dal2°mese(2000mg+40mg)/giorno

Prelievovenoso: EmocromoconformulaleucocitariaColesterolototale,LDL,HDLTrigliceridiAST,ALT,γGT,CPKUricemiaGlicemiaPCRultrasensibileLipoproteina(a)

* Valutazione clinica ad ogni controllo: anamnesi esame obbiettivo

Popolazione,n=8

Laterapiaèstataassuntaallasera,primadicoricarsi,accompagnatadaunospunXno.

0

10

20

30

40

50

60

70

80

basale 3mesi 6mesi

Risulta'HDL

ValoridiHDLvalutaXinassenzaditerapiaconacidonicoXnico

ValoridiHDLvalutaXinterapiaconacidonicoXnico

T1 T2T3

T2NT3N

T1N

HDL[mg/dl]

p

T1N(basale) 46,5(26-67)

T2N 57,5(41-87) 0,195*

T3N 69,5(48-91) 0,013*

HDL[mg/dl] p

T1(basale) 52(33-71)

T2 43(29-57) 0,195*

T3 51,5(26-62) 0,878*

Popolazione,n=8

p for trend=0,041

52,8% T1N T3N

*pversobasale *pversobasale

mg/dl

0

20

40

60

80

100

120

basale 3mesi 6mesi

Risulta'Trigliceridi

ValoriditrigliceridivalutaXinassenzaditerapiaconacidonicoXnico

ValoriditrigliceridivalutaXinterapiaconacidonicoXnico

T1T2

T3

T2N T3N

T1N

Trigliceridi[mg/dl]

p

T1N(basale) 96(59-197)

T2N 74(37-111) 0,130*

T3N 74(41-88) 0,043*

Trigliceridi[mg/dl] p

T1(basale) 94(71-202)

T2 103(74-203) 0,382*

T3 97,5(53-246) 0,574*

Popolazione,n=8

p for trend=0,091

33,9%

T1N T3N


mg/dl

Risulta'Lipoproteina(a)

Valoridilipoproteina(a)valutaXinassenzaditerapiaconacidonicoXnico

Valoridilipoproteina(a)valutaXinterapiaconacidonicoXnico

0

200

400

600

800

1000

1200

1400

1600

1800

basale 3mesi 6mesi

T1T2

T3

T2NT3N

T1N

Lpa(a)[mg/l]

p

T1N(basale) 1455(710-1870)

T2N 1025(410-1420) 0,021*

T3N 915(508-1300) 0,013*

Lpa(a)[mg/l] p

T1(basale) 1510(610-1840)

T2 1620(580-2190) 0,65*

T3 1430(650-2300) 0,93*

Popolazione,n=8

p for trend 0,016

34,2%

T1N T3N


mg/l

0

20

40

60

80

100

120

basale 3mesi 6mesi

LDL

125

130

135

140

145

150

155

160

165

170

basale 3mesi 6mesi

Colesterolo totale

ValorivalutaXinassenzaditerapiaconacidonicoXnicoValorivalutaXinterapiaconacidonicoXnico

LDL[mg/dl]

p

T1N(basale) 84(74-167)

T2N 66(43-149) 0,054*

T3N 90(57-118) 0,432*

LDL[mg/dl] p

T1(basale) 92,5(69-161)

T2 93(66-181) 0,65*

T3 79,5(53-180) 0,93*

Colesterolototale[mg/dl]

p*

T1N(basale) 158(116-294)

T2N 141(108-328) 0,2*

T3N 163(113-314) 0,9*

Colesterolototale[mg/dl] p*

T1(basale) 164(134-307)

T2 165(147-282) 0,9*

T3 166(116-342) 0,8*

*pversobasale

*pversobasale

pfortrend=0,180

mg/dl

mg/dl

pfortrend=0,180

0

0,2

0,4

0,6

0,8

1

1,2

basale 3mesi 6mesi

Crea'nina

270280290300310320330340

basale 3mesi 6mesi

Fibrinogeno

85

90

95

100

105

basale 3mesi 6mesi

Glicemia

010203040

basale 3mesi 6mesi

ALT

0

10

20

30

40

basale 3mesi 6mesi

AST

0

10

20

30

basale 3mesi 6mesi

γGT

0

0,01

0,02

0,03

basale 3mesi 6mesi

PCRultrasensibile

4

4,5

5

5,5

basale 3mesi 6mesi

Uricemia

0

50

100

150

200

basale 3mesi 6mesi

CPK

ProfiloditollerabilitàdellaterapiaconacidonicoXnico+laropiprant

mg/dlmg/dl mg/dl

U/L U/LU/L

U/L mg/dlmg/L

T1N(basale) T2N(3mesi) T3N(6mesi)

Effeyavversi

Iniziodellaterapia(1-4giorniditerapia,dosaggio1000mg/20mg):“flushing”localizzatoalvolto,altroncoeagliarXsuperioridilieveintensitàedibrevedurata(8pazienX);prurito(3pazienX);sonnolenza(1paziente).

Passaggioadosaggioterapeu'co(1mesediterapia,dosaggio2000mg/40mg):“flushing”localizzatoalvolto,altroncoeagliarXsuperioridilieveintensitàedibrevedurata(5pazienX);prurito(3pazienX);sonnolenza(1paziente);sXpsi(1paziente).

Passaggioadosaggioterapeu'co(5mesiditerapia,dosaggio2000mg/40mg):mialgiadilieveenXtà,nonassociataadinnalzamentodelCPK(1paziente);lieveepigastralgia(1paziente).

Nessuneventoavversograveregistrato.Nonsièresanecessarialasospensionedellaterapiaenessunpazientehainterropovolontariamentelaterapia.

Followup12 mesi

020406080100120140160180

Basale TN1 TN2 TN3 TN4

colesterolototale

0

10

20

30

40

50

60

70

80


HDL

0102030405060708090


LDL

0

20

40

60

80

100

120


trigliceridi

mg/dl mg/dl

mg/dlmg/dlP=0,040

P=0,054

P=0,038

0

200

400

600

800

1000

1200

1400

1600


lipoproteina(a)

Followup12 mesi

mg/dl

5/8pazienXhannoraggiuntolivellidiLp(a)<600mg/dldopo1annoditerapia

P=0,006

P=0,001

Conclusioni

In una popolazione ad alto rischio cardiovascolare,sovopostaaproceduraafereXca, lasomministrazionedi acido nicoXnico/laropiprant è in grado diowmizzare l'assepo lipidico con il significa'voaumentodei livelli di colesteroloHDL e la riduzionedeilivellidiLp(a).

Lostudio,tuvoraincorso,ciconsenXràdivalutaresela somministrazione di acido nicoXnico oltre allaterapia standard possa consenXre di allungare il'ming fra le procedure afere'che in pazien'seleziona'.

Mattiuzzi C, J Thromb Thrombol 2014

J Intern Med 2013

Documents

Lp(a) hyperlipoproteinemia - mightymedic.org · Lp(a) and lipids in relation to inflammation in rheumatoid arthritis. Clin reumatol 2000 High Lp(a) levels in chronic hemodialysis