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Liječnički vjesnik, Vol. 146 No. 1-2, 2024.

Pregledni rad

https://doi.org/10.26800/LV-146-1-2-7

Elevated lipoprotein (a) – an independent risk factor for cardiovascular disease – recommendations for measuring and treatment

Željko Reiner ; Klinički bolnički centar Zagreb *
Davor Miličić
Dunja Rogić
Šime Manola
Alen Ružić
Silvija Canecki-Vražić
Ivica Kristić
Lidija Bilić Zulle
Lovorka Đerek
Vatroslav Šerić
Leida Tandara

* Dopisni autor.

Puni tekst: hrvatski pdf 1.691 Kb

str. 49-61

preuzimanja: 1.892

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Sažetak

The guidelines of international professional societies indicate that elevated concentration of lipoprotein(a) [Lp(a)] in the blood is a long-term independent risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), as well as for calcification stenosis of the aortic valves. The aim of this document which was produced as a consensus document of the authors who are national experts in the field is to present the latest knowledge about diagnostics and current treatment options for patients with elevated Lp(a) concentrations in the blood, which are modest at the moment, but also to indicate future treatment options that are on the horizon. The conclusion that can be made on the basis of current knowledge indicates that there is an immediate benefit for patients in measuring the concentration of Lp(a), even if fully effective pharmacological treatment is not yet available. Measurement of Lp(a) facilitates faster and more reliable identification of patients with high cardiovascular risk
and better management of that risk, i.e. it indicates the need for more intensive reduction and treatment of other risk factors for ASCVD if Lp(a) is significantly increased. It is recommended to express the concentration of Lp(a) in nmol/L measured by methods calibrated with calibrators whose concentration is expressed in nmol/L.

Ključne riječi

CARDIOVASCULAR DISEASES – epidemiology,etiology, prevention and control; ATHEROSCLEROSIS – epidemiology,etiology, prevention and control; SECONDARY PREVENTION; LIPOPROTEIN(a) – blood, genetics; AORTIC VALVE STENOSIS – epidemiology,etiology, prevention and control; CALCINOSIS; CHOLESTEROL, LDL – u krvi; HYPERLIPIDEMIAS – drug therapy; PCSK9 INHIBITORS – therapeutic use; RNA, SMALL INTERFERING – therapeutic use; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS – therapeutic use; RISK FACTORS

Hrčak ID:

314685

URI

https://hrcak.srce.hr/314685

Datum izdavanja:

27.2.2024.

Podaci na drugim jezicima: hrvatski

Posjeta: 3.300 *

License (open-access, ):

CC BY-NC-ND (Attribution, Non Commercial, No Derivs)

License (open-access):

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License (open-access):

The Medical Journal is an open access journal. The content of the magazine is available in its entirety free of charge. The contents of the Medical Journal may be reproduced with the quotation "taken from the Medical Journal". Users may not use the materials for commercial purposes, may not modify, redesign or rework the material.

Publication date: 27 February 2024

Volume: 146

Pages: 49-61

DOI: 10.26800/LV-146-1-2-7

Article Information (continued)

Categories:

Subject: Pregledni rad

Categories:

Subject: Review article

Keywords:

Keyword: KARDIOVASKULARNE BOLESTI – epidemiologija, etiologija, prevencija

Keyword: ATEROSKLEROZA – epidemologija, etiologija, prevencija

Keyword: SEKUNDARNA PREVENCIJA

Keyword: LIPOPROTEIN(a)- genetika, u krvi

Keyword: STENOZA AORTNIH ZALISTAKA – epidemiologija, etiologija, prevencija

Keyword: KALCINOZA

Keyword: LDL KOLESTEROL – u krvi

Keyword: HIPERLIPIDEMIJE – farmakoterapija

Keyword: PCSK9 INHIBITORI – terapijska uporaba

Keyword: MALA INTERFERIRAJUĆA RNK – terapijska uporaba

Keyword: STATINI – terapijska uporaba

Keyword: ČIMBENICI RIZIKA

Keywords:

Keyword: CARDIOVASCULAR DISEASES – epidemiology,etiology, prevention and control

Keyword: ATHEROSCLEROSIS – epidemiology,etiology, prevention and control

Keyword: SECONDARY PREVENTION

Keyword: LIPOPROTEIN(a) – blood, genetics

Keyword: AORTIC VALVE STENOSIS – epidemiology,etiology, prevention and control

Keyword: CALCINOSIS

Keyword: CHOLESTEROL, LDL – u krvi

Keyword: HYPERLIPIDEMIAS – drug therapy

Keyword: PCSK9 INHIBITORS – therapeutic use

Keyword: RNA, SMALL INTERFERING – therapeutic use

Keyword: HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS – therapeutic use

Keyword: RISK FACTORS

Povećani lipoprotein(a) – neovisni čimbenik kardiovaskularnog rizika – preporuke za određivanje i liječenje

Translated Title (en): Elevated lipoprotein (a) – an independent risk factor for cardiovascular disease – recommendations for measuring and treatment

Željko Reiner

Email: zreiner@kbc-zagreb.hr

Davor Miličić

Dunja Rogić

Šime Manola

Alen Ružić

Silvija Canecki-Vražić

Ivica Kristić

Lidija Bilić Zulle

Lovorka Đerek

Vatroslav Šerić

Leida Tandara

 

Klinički bolnički centar Zagreb

Abstract

Smjernice međunarodnih stručnih društava ukazuju da je povišena koncentracija lipoproteina(a) [Lp(a)] u krvi dugoročni neovisni čimbenik rizika za razvitak aterosklerotske kardiovaskularne bolesti (ASKVB), kao i za kalcifikacijsku stenozu aortnih zalistaka. Cilj je ovog članka koji je rezultat konsenzusa nacionalnih stručnjaka iz tog područja predstaviti najnovije spoznaje o dijagnostici i sadašnjim mogućnostima liječenja bolesnika s povišenom koncentracijom Lp(a) u krvi koje su u ovom trenutku skromne, ali i naznačiti buduće mogućnosti liječenja koje su na pomolu. Zaključak koji se može postaviti na temelju dosadašnjih spoznaja upućuje da postoji neposredna korist za bolesnike u mjerenju koncentracije Lp(a), čak i ako potpuno učinkovito farmakološko liječenje još nije dostupno. Mjerenje Lp(a) olakšava bržu i pouzdaniju identifikaciju bolesnika s visokim kardiovaskularnim rizikom i bolje upravljanje tim rizikom, odnosno upućuje na potrebu intenzivnijeg smanjivanja i liječenja ostalih čimbenika rizika za ASKVB ako je Lp(a) značajnije povećan. Izražavanje koncentracije Lp(a) preporučuje se u nmol/L izmjerene metodama kalibriranim kalibratorima čija je koncentracija izražena u nmol/L.

Translated Abstract

The guidelines of international professional societies indicate that elevated concentration of lipoprotein(a) [Lp(a)] in the blood is a long-term independent risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), as well as for calcification stenosis of the aortic valves. The aim of this document which was produced as a consensus document of the authors who are national experts in the field is to present the latest knowledge about diagnostics and current treatment options for patients with elevated Lp(a) concentrations in the blood, which are modest at the moment, but also to indicate future treatment options that are on the horizon. The conclusion that can be made on the basis of current knowledge indicates that there is an immediate benefit for patients in measuring the concentration of Lp(a), even if fully effective pharmacological treatment is not yet available. Measurement of Lp(a) facilitates faster and more reliable identification of patients with high cardiovascular risk and better management of that risk, i.e. it indicates the need for more intensive reduction and treatment of other risk factors for ASCVD if Lp(a) is significantly increased. It is recommended to express the concentration of Lp(a) in nmol/L measured by methods calibrated with calibrators whose concentration is expressed in nmol/L.

Povećani lipoprotein(a) – neovisni čimbenik kardiovaskularnog rizika – preporuke za određivanje i liječenje

Elevated lipoprotein (a) – an independent risk factor for cardiovascular disease – recommendations for measuring and treatment

Željko Reiner1,2 (https://orcid.org/0000-0002-4932-4212), Davor Miličić3,4, Dunja Rogić5,6, Šime Manola7,8, Alen Ružić9,10, Silvija Canecki-Varžić11,12, Ivica Kristić13, Bilić-Lidija Zulle14,10, Lovorka Đerek15, Vatroslav Šerić16,12, Leida Tandara17,18

1 Zavod za bolesti metabolizma, Klinički bolnički centar Zagreb

2 Spomen bolnica Poljske majke i znanstveni institut, Lodz, Poljska

3 Klinika za bolesti srca i krvnih žila, Klinički bolnički centar Zagreb

4 Medicinski fakultet Sveučilišta u Zagrebu

5 Klinički zavod za laboratorijsku dijagnostiku, Klinički bolnički centar Zagreb

6 Farmaceutsko-biokemijski fakultet Sveučilišta u Zagrebu

7Zavod za bolesti srca i krvnih žila, Klinička bolnica Dubrava

8 Stomatološki fakultet Sveučilišta u Zagrebu

9 Klinički bolnički centar Rijeka

10 Medicinski fakultet Sveučilišta u Rijeci

11 Klinika za internu medicinu, Klinički bolnički centar Osijek

12 Medicinski fakultet Sveučilišta Josipa Jurja Strossmayera u Osijeku

13 Klinika za bolesti srca i krvnih žila, Klinički bolnički centar Split

14 Klinički zavod za laboratorijsku dijagnostiku, Klinički bolnički centar Rijeka

15 Klinički zavod za laboratorijsku dijagnostiku, Klinička bolnica Dubrava

16 Klinički zavod za laboratorijsku dijagnostiku, Klinički bolnički centar Osijek

17 Zavod za medicinsko-laboratorijsku dijagnostiku, Klinički bolnički centar Split

18 Medicinski fakultet Sveučilišta u Splitu

Deskriptori KARDIOVASKULARNE BOLESTI – epidemiologija, etiologija, prevencija; ATEROSKLEROZA – epidemologija, etiologija, prevencija; SEKUNDARNA PREVENCIJA; LIPOPROTEIN(a)- genetika, u krvi; STENOZA AORTNIH ZALISTAKA – epidemiologija, etiologija, prevencija; KALCINOZA; LDL KOLESTEROL – u krvi; HIPERLIPIDEMIJE – farmakoterapija; PCSK9 INHIBITORI – terapijska uporaba; MALA INTERFERIRAJUĆA RNK – terapijska uporaba; STATINI – terapijska uporaba; ČIMBENICI RIZIKA

SUMMARY

The guidelines of international professional societies indicate that elevated concentration of lipoprotein(a) [Lp(a)] in the blood is a long-term independent risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), as well as for calcification stenosis of the aortic valves. The aim of this document which was produced as a consensus document of the authors who are national experts in the field is to present the latest knowledge about diagnostics and current treatment options for patients with elevated Lp(a) concentrations in the blood, which are modest at the moment, but also to indicate future treatment options that are on the horizon. The conclusion that can be made on the basis of current knowledge indicates that there is an immediate benefit for patients in measuring the concentration of Lp(a), even if fully effective pharmacological treatment is not yet available. Measurement of Lp(a) facilitates faster and more reliable identification of patients with high cardiovascular risk and better management of that risk, i.e. it indicates the need for more intensive reduction and treatment of other risk factors for ASCVD if Lp(a) is significantly increased. It is recommended to express the concentration of Lp(a) in nmol/L measured by methods calibrated with calibrators whose concentration is expressed in nmol/L.

Adresa za dopisivanje:

Akademik prof. dr. sc. Željko Reiner, dr. med., https://orcid.org/0000-0002-4932-4212, Klinički bolnički centar Zagreb, Kišpatićeva 12, 10000 Zagreb, e-pošta: zreiner@kbc-zagreb.hr

Primljeno 22. svibnja 2023., prihvaćeno 6. studenoga 2023.

Lipoprotein(a) je lipoproteinska čestica jedinstvene strukture koja osim apolipoproteina B100 (apoB100) dodatno sadrži i specifičan apolipoprotein (a) – apo(a). (1) To je čestica promjera <70 nm koja je vrlo nalik čestici lipoproteina niske gustoće (LDL), a sadrži podjednaku količinu kolesterola. Lp(a) može slobodno prolaziti kroz endotelnu barijeru gdje se može, slično LDL česticama, zadržati u subendotelnom prostoru, tj. unutar arterijske stijenke i potaknuti nastanak aterosklerotičnih nakupina te posljedično aterosklerotične kardiovaskularne bolesti (ASKVB). (2) Gotovo 90% koncentracije Lp(a) genski je uvjetovano i to na LPA lokusu, s izraženim varijacijama u raznim populacijama. (3, 4) Postoji više od 40 izoformi Lp(a). (5) Budući da je apo(a) dobrim dijelom homologan plazminogenu, Lp(a) kompetitivnom inhibicijom djeluje i protrombogeno pa time doprinosi procesu aterotromboze.

Epidemiološka opservacijska ispitivanja upućuju prilično nedvojbeno na povezanost između povišenog Lp(a) i povećanog rizika od ASKVB-a te kalcifikacijske stenoze aortnih zalistaka (engl. AVS). Tako povećani Lp(a) predstavlja 3 – 4 puta povećani rizik akutnog infarkta miokarda, 3 puta veći rizik aortne stenoze, 1,6 puta veći rizik ishemijskog moždanog udara, 1,4 puta veći rizik periferne arterijske bolesti, 1,5 puta veći rizik kardiovaskularne smrtnosti i 1,2 puta veći rizik ukupne smrtnosti. (6) Nedavna genetska ispitivanja potvrdila su ovu povezanost. Europsko društvo za aterosklerozu (EAS) smatra da razina Lp(a) od 50 mg/dL (~125 nmol/L) ili viša predstavlja povećani kardiovaskularni rizik. Takve vrijednosti ima otprilike 20% do 25% globalne populacije. (7) Lp(a) je, dakle, neovisni, nasljedni, uzročni čimbenik rizika za ASKVB.

Cijeli niz svjetskih stručnih društava načinio je kliničke smjernice koje preporučuju određivanje Lp(a) (Table 1). (8–13) Općenito uzevši, postoji značajna usklađenost između svih tih različitih smjernica jer sve preporučuju određivanje Lp(a) kao dio kliničke procjene visokorizičnih osoba. Međutim, većina smjernica preporučuje mjerenje koncentracije Lp(a) jednom u životu svake osobe s obzirom na to da koncentracija Lp(a) ostaje uglavnom stabilna tijekom života. (12) Određivanje koncentracije Lp(a) koristi za:

identifikaciju pojedinaca s vrlo visokim naslijeđenim koncentracijama Lp(a) u krvi;

određivanje obiteljskog rizika;

klasifikaciju ljudi koji su na granici između umjerenoga i visokoga kardiovaskularnog rizika;

optimiziranje liječenja drugih čimbenika rizika ASKVB-a radi smanjenja ukupnog rizika za ASKVB.

Budući da postoje i negenetski čimbenici (Table 2) koji mogu utjecati na koncentraciju Lp(a), kao što su primjerice bolesti jetre, akutne infekcije, kronične bolesti bubrega, dijabetes, u pojedinim slučajevima potrebno je ipak ponoviti mjerenje Lp(a). (7, 14)

Patofiziologija Lp(a)

Lp(a) potiče razvoj ASKVB-a i kalcificiranu stenozu aortnog zaliska (AVS) putem četiriju mehanizama: poticanja vaskularne upale, aterogeneze, kalcifikacije i trombogeneze. Lp(a) ulazi u intimu arterija gdje se oksidira, što rezultira stvaranjem reaktivnih kisikovih spojeva koje izazivaju upalu putem pojačane propusnosti endotela, dijapedezu, proizvodnju citokina, apoptozu i remodeliranje vaskularne stijenke. Makrofagi unose u sebe oksidirani LDL dio lipoproteina(a), pretrpavaju se kolesterolom iz Lp(a) čestica, te se pretvaraju u tzv. pjenaste stanice i potiču stvaranje aterosklerotskog plaka. Lp(a) je jedini lipoprotein koji sadrži apoB i oksidirane fosfolipide koji se talože na oštećenim stijenkama arterija i aortnim zaliscima kada su koncentracije Lp(a) u plazmi visoke, uzrokuje endotelnu disfunkciju, nakupljanje lipida, kalcifikaciju i upalu. Povišene razine Lp(a) mogu imati protrombotski/antifibrinolitički učinak budući da apolipoprotein(a) nalikuje i plazminogenu i plazminu, ali nema fibrinolitičku aktivnost, ili mogu ubrzati aterosklerozu jer je čestica Lp(a) bogata kolesterolom, ili pak mogu uzrokovati oboje. (3, 7)

Lp(a) u primarnoj i sekundarnoj prevenciji

U primarnoj prevenciji povišeni Lp(a) povezuje se s ishemijskim moždanim udarom, infarktom miokarda i zatajivanjem srca kao dio neliječene ASKVB, ali i sa stenozom aortnog zaliska (engl. AVS) te kardiovaskularnom smrtnošću i ukupnom smrtnošću (Figure 1, Table 3). Koncentracije Lp(a) u plazmi iznad 75. percentile povećavaju rizik od stenoze aortnog zaliska i infarkta miokarda dok su još više koncentracije (>90. percentile) povezane s povećanim rizikom od zatajivanja srca. Rizik od kardiovaskularne smrtnosti i ishemijskog moždanog udara povećava se samo kad su koncentracije vrlo visoke (>95 percentile). (13) U primarnoj prevenciji ključno je napraviti individualnu procjenu čimbenika rizika za obolijevanje od ASKVB-a uključujući ranu pojavu ASKVB-a u obitelji te misliti na subkliničku aterosklerozu. (14)

U sekundarnoj prevenciji povišeni Lp(a) u krvi povezan je s povećanim rizikom od velikih štetnih kardiovaskularnih događaja, iako su razna ispitivanja izvijestila o određenim razlikama u rezultatima. (53) AIM-HIGH ispitivanje pokazalo je otprilike 90% veći rizik za velike kardiovaskularne događaje kada je Lp(a) bio >75. percentile (>125 nmol/L) u usporedbi s manjim koncentracijama, čak i kad je LDL-kolesterol bio oko 65 mg/dL (1,67 mmol/L). (54) U metaanalizi čiji je cilj bio procijeniti prognostičku mogućnost korištenja razina lipoproteina(a) u bolesnika s bolesti koronarnih arterija liječenih statinima, razine Lp(a) >80. percentile bile su značajno prediktivne za rekurentne događaje [omjer izgleda (OR): 1,40, 95% interval pouzdanosti (CI): 1,15–1,71], ali ne i kada je početna vrijednost LDL-kolesterola bila <130 mg/dL (<3,35 mmol/L). (55) U Copenhagen City Heart Study (CCHS) rizik od velikih kardiovaskularnih događaja bio je veći kod Lp(a) ≥ 50 mg/dL u odnosu na koncentracije <10 mg/dL, čak i kada su razine LDL-kolesterola bile relativno niske, tj. <70 mg/dL (<1,8 mmol/L). (56)

Povezanost Lp(a) i stenoze aortnog zaliska

Utvrđeno je da lokus LPA bitno doprinosi riziku od stenoze aortnog zaliska (engl. AVS). Visoka koncentracija Lp(a) povezana je s mikrokalcifikacijom i makrokalcifikacijom aortnog zaliska, posebice u relativno mladih zdravih osoba (45 – 54 godine) kod kojih je rizik povećan tri puta ako je Lp(a) >80. percentile u odnosu na osobe sa nižim koncentracijama Lp(a) (15,8% u odnosu na 4,3%). Visoka koncentracija Lp(a) također može pospješiti bržu progresiju aortalne stenoze koja rezultira ranijom zamjenom aortnog zaliska i gdjekada, posebno ako se ne liječi, smrću (Table 4). (13) U nedavno objavljenom ispitivanju na 143.087 Islanđana dokazana je snažna povezanost AVS-a (i ishemijske koronarne bolesti srca te zatajivanja srca) s izmjerenim i imputiranim koncentracijama lipoproteina(a) i brojem ponavljanja KIV2. (21)

Do životne dobi od dvije godine LPA gen je potpuno izražen. Razine Lp(a) koje imaju odrasle osobe obično se postižu s oko pet godina, ali se mogu se povećavati do odrasle dobi. (13)

Izazovi određivanja Lp(a)

Heterogenost veličine apo(a) zbog različitog broja ponavljanja tzv. petlja (kringle) IV-2 domena uzrokuje interindivindualnu različitost veličina Lp(a) čestica. Ova činjenica predstavlja izazov za točnost mjerenja Lp(a) zbog nemogućnosti točne kalibracije imunokemijskih metoda. Zbog toga je Međunarodno udruženje za kliničku kemiju i laboratorijsku medicinu (engl. IFCC) u suradnji s Odborom za biološke standarde Svjetske zdravstvene organizacije (engl. WHO) još 2001. godine kreiralo i preporučilo jedinstveni zajednički kalibrator te obvezu izražavanja rezultata u nmol/L radi standardizacije mjernih metoda. Mjerenje molarne koncentracije te kalibracija u više koncentracijskih razina u najvećoj mogućoj mjeri zaobilazi heterogenost mjerenja mase. Mjerenjem Lp(a) u molarnim jedinicama (nmol/L) iskazuje se količina čestica Lp(a), a ne njihova masa. (7)

U idealnom slučaju, imunokemijske metode mjerenja Lp(a) trebale bi koristiti protutijela za jedinstveni epitop Lp(a) čestice različit od varijabilne petlje IV-2 domene. Međutim, proizvodnja takvih protutijela nije jednostavna te zbog toga današnje metode rabe protutijela koja prepoznaju ove ponavljajuće epitope i stoga potencijalno podcjenjuju ili precjenjuju koncentraciju Lp(a) ovisno o prisutnosti malih ili velikih izoformi. Djelomično se ovaj problem zaobilazi korištenjem dobro definirane kalibracijske krivulje (najmanje pet različitih koncentracija kalibratora), kako je navedeno u preporukama IFCC-a. (57)

Mogu li se koncentracije Lp(a) preračunati iz jedinica mase u molarne jedinice i obrnuto?

Preporučene metode za mjerenje Lp(a) su one koje su kalibrirane u nmol/L. Ne preporučuje se rabiti faktore konverzije iz g/L ili mg/dl u nmol/L s obzirom na heterogenost veličine čestica. Aterogeni rizik izravno je povezan s brojem Lp(a) čestica, a isti se izražava isključivo kao molarna koncentracija. Zbog toga bi svi klinički laboratoriji trebali mjeriti Lp(a) metodama preporučenim od strane relevantnih međunarodnih stručnih udruga, a to su metode čiji je rezultat izražen u nmol/L.

Shodno navedenom, ne preporučuje se korištenje standardnog faktora za pretvorbu, odnosno preračunavanje mg/dL u nmol/L, s obzirom na heterogenost mjerenih čestica i različitost mjernih metoda. U situacijama kada se obje jedinice koriste u kliničkoj praksi, 2,0 – 2,5 je samo „najbolja pretpostavka“ za faktor pretvorbe (mg/dL u nmol/L). Istraživanja koja su spomenuta u ovom članku sadrže koncentracije Lp(a) u onim jedinicama kako su objavljene u izvornim publikacijama. Za opće izjave koje se odnose na koncentraciju Lp(a), u mg/dL i nmol/L korišten je približan faktor pretvorbe od 2,0 – 2,5, uz sva ograničenja koja su ranije spomenuta.

Koristi određivanja Lp(a) za bolesnike

Određivanje Lp(a) olakšava identifikaciju i bolju skrb o bolesnicima s visokim kardiovaskularnim rizikom. Pojedinci s vrlo visokom razinom Lp(a) (>430 nmol/L; ~180 mg/dL) imaju više od tri puta povećan rizik od ASKVB-a, što se može usporediti s rizikom koji imaju bolesnici s heterozigotnom porodičnom hiperkolesterolemijom. Iako je vrlo visoki Lp(a) 2,5 puta češći od heterozigotne porodične hiperkolesterolemije (1:100 u odnosu na 1:250), velika većina bolesnika ostaje nedijagnosticirana jer standardno određivanje lipida, odnosno lipoproteina ne uključuje mjerenje Lp(a). (58) Konkretno, spoznaja o povišenom Lp(a) treba uputiti liječnike na obraćanje veće pozornosti i intenzivnije liječenje drugih čimbenika rizika za ASKVB koji se mogu uspješno liječiti, ali i izvođenje kaskadnog probira porodice. Tako primjerice bolesnici s visokim koncentracijama Lp(a) koji se liječe statinima zbog povećanog LDL-kolesterola neće postizati ono sniženje LDL-kolesterola koje bi se moglo očekivati i imaju veći rezidualni kardiovaskularni rizik unatoč liječenju maksimalno podnošljivim dozama statina čak i kad uzimaju statin u kombinaciji s ezetimibom. Međutim, ti će bolesnici imati veću relativnu korist od terapije inhibitorom PCSK9 ili inklisiranom jer ti lijekovi mogu smanjiti Lp(a) za 15–30%. (59, 60) Štoviše, s obzirom na to da se Lp(a) prenosi autosomno dominantno, bliski rođaci osoba s povišenim Lp(a) potencijalno bi se mogli otkriti kaskadnim probirom i, ako je potrebno, započeti liječiti u znatno ranijoj životnoj dobi. Primjerice, smjernica HEART UK preporučuje da jedna od ciljnih populacija budu srodnici u prvom koljenu bolesnika s povišenim Lp(a). Osim toga, ranija identifikacija takvih bolesnika omogućuje liječnicima da ranije stupe u kontakt s bolesnikom i njegovim ili njenim bliskim srodnicima i djeluju na povećanje njihove svijesti o činjenici da je povišeni Lp(a) nasljedni uzrok preuranjene ASKVB. (61)

Iako randomizirana ispitivanja s lijekovima koji smanjuju Lp(a) za 20 – 30%, primjerice niacin, nisu pokazala da smanjenje Lp(a) smanjuje rizik od aterosklerotske KVB, novija ispitivanja s inhibitorima PCSK9 upućuju da bi smanjenje Lp(a) ipak moglo smanjiti rizik ASKVB-a. (62)

Kliničke smjernice: što učiniti s bolesnikom koji ima povišen Lp(a)?

U nedostatku odobrenih specifičnih lijekova za snižavanje Lp(a), preporučuje se rana i intenzivna skrb te liječenje drugih čimbenika kardiovaskularnog rizika u osoba s povišenim razinama Lp(a), u skladu s većinom smjernica. (13)

Sukladno tomu valja individualizirati pristup liječenju povišenog LDL-kolesterola, arterijskog krvnog tlaka, glukoze (liječenje dijabetesa), debljine i poticati zdrav način života, uzimajući u obzir početni kardiovaskularni rizik i neliječenu razinu Lp(a), sve radi smanjenja rizika za ASKVB. To može smanjiti povećani rizik uzrokovan povišenim Lp(a).

Preporučuje se obvezatno liječiti LDL-kolesterol sukladno važećim smjernicama. Iako statini mogu neznatno povisiti razinu Lp(a), liječenje statinima ne smije se prekinuti budući da korist od liječenja statinima u bolesnika s visokim Lp(a) koji imaju i povišeni LDL-kolesterol daleko nadmašuje svaki potencijalni rizik povezan s umjerenim povećanjem razine Lp(a) uzrokovanim statinima. Dapače, valja intenzivirati sniženje jako povećanog LDL-kolesterola ovisno o razinama Lp(a) kako bi se smanjio rizik ASKVB-a. (13)

Afereza lipoproteina može doći u obzir u bolesnika s vrlo visokim Lp(a) koji imaju uznapredovalu ASKVB unatoč optimalnom liječenju drugih čimbenika rizika, uključujući i povećeni LDL-kolesterol. (63)

Preporučuje se liječiti PCSK9 inhibitorima (alirokumab ili evolokumab) ili miRNK (inklisiran) bolesnike s miješanom dislipidemijom i/ili rezidualnim kardiovaskularnim rizikom kod kojih maksimalno podnošljivim dozama statina s ezetimibom ili bez njega nije postignuta ciljna koncentracija LDL-kolesterola. (64–67)

Niacin se ne preporučuje za liječenje povišenog Lp(a) s obzirom na nedostatak dokaza o kliničkoj koristi u dva klinička ispitivanja, usprkos činjenici da niacin donekle snižava Lp(a). (13, 68)

Trenutačni podatci također ne podupiru ciljanu upotrebu aspirina kod povećane koncentracije Lp(a). (13)

Postoje istraživanja koja upućuju da bi uzimanje dodataka hrani poput lanenih sjemenki moglo smanjiti razine Lp(a), no stvarna korist od toga zasada je još upitna. (69)

Nedavno je pokazano da barijatrijska kirurgija u debelih osoba smanjuje Lp(a), no nema izravnih dokaza da to također smanjuje i rizik za ASKVB. (70)

Kako pristupiti izazovu povišene koncentracije lipoproteina(a)?

Preporuke:

Mjerenje Lp(a) treba rutinski uključiti kao dio početnoga lipidnog profila. Načelno, Lp(a) treba odrediti svakoj osobi jednom u životu.

Povišenom koncentracijom Lp(a) treba smatrati onu iznad 100 – 125 nmol/L, a vrijednost Lp(a) treba uvijek izražavati u nmol/L.

Predlažemo da se lipoprotein(a) za sada određuje u kliničkim bolničkim centrima i kliničkim bolnicama, te da druge ustanove dostavljaju uzorke u kliničke bolničke centre i kliničke bolnice.

Lipoprotein(a) bi trebalo učiniti lako dostupnim u informatičkim sustavima (IBIS) svih kliničkih bolničkih centara i kliničkih bolnica.

Ciljana populacija:

– bolesnicima u sekundarnoj prevenciji koji imaju progresiju i/ili simptomatsku ASKVB unatoč dobro kontroliranom LDL-kolesterolu i drugim čimbenicima rizika te onima s porodičnom hiperkolesterolemijom treba obvezatno odrediti Lp(a).

– u primarnoj prevenciji preporučujemo da svima u sklopu trenutno predloženoga Nacionalnog preventivnog programa obiteljska medicina postupno odredi Lp(a) tijekom slijedeće dvije do tri godine.

Preporučuje se obiteljsko savjetovanje pri dokazu povišenog Lp(a).

Potrebno je obavijestiti bliske krvne rođake o povećanom riziku za ASKVB; ponuditi kaskadno testiranje za visoki Lp(a) i savjetovanje prije i poslije testiranja bliskim rođacima indeksnog bolesnika.

Potrebno je promicati korištenje MKB kodova za povišeni Lp(a) u bolnicama, primarnim ustanovama i kliničkim registrima.

MKB-10 – dijagnostička šifra E78.41: Povišen Lp(a) te MKB-10 – dijagnostička šifra Z83.430: Obiteljska povijest povišenog Lp(a)

Potrebno je uključiti Lp(a) u strategije procjene rizika za ASKVB.

U svih s povećanim Lp(a) potrebno je procijeniti apsolutni rizik za ASKVB.

Potrebno je obratiti pozornost na rizične čimbenike ponašanja i osigurati savjete o zdravom načinu života i prehrane.

Potrebno je razgovarati o rizicima i koristima terapije lijekovima za čimbenike kardiovaskularnog rizika, uzimajući u obzir vrijednosti čimbenika rizika i sklonosti bolesnika.

Potrebno je ponuditi pregled kod specijalista svim bolesnicima s povišenim Lp(a) i visokim rizikom od ASKVB-a.

Laboratorijska izvješća

Potrebno je upozoriti kliničare na važnost povišene koncentracije Lp(a) iznad 100 nmol/L.

Klinički registri

Svi bolesnici s izrazito visokim Lp(a) i oboljeli krvni rođaci trebali bi biti uključeni u kvalitetan klinički registar koji valja uspostaviti.

Suradnja s udrugama bolesnika

Potrebno je uspostaviti suradnju s udrugama bolesnika u svrhu uspješnijeg zagovaranja poboljšanja skrbi za osobe s visokim Lp(a): to bi trebalo uključivati podizanje svijesti javnosti, osiguravatelja (Hrvatski zavod za zdravstveno osiguranje) i Ministarstva zdravstva, provedbu isplativih strategija testiranja i pristup novim načinima liječenja koji dolaze.

Potrebno je raditi na podizanju svijesti društva u cjelini o važnosti povišene koncentracije Lp(a), što uključuje društvene medije, zdravstvene aplikacije, web stranice i webinare.

KRATICE

ASKVB, aterosklerotska kardiovaskularna bolest; ASO, antisense oligonukleotid; AVS, stenoza aortne valvule; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; LDL-K, kolesterol u lipoproteinima niske gustoće; Lp(a), lipoprotein(a); KV, kardiovaskularni; MACE, veliki štetni kardiovaskularni događaji; miRNK, mala interferirajuća RNK; MKB, Međunarodna klasifikacija bolesti; PCSK9, proprotein konvertaza keksin/suptilizin tip 9

INFORMACIJE O SUKOBU INTERESA

Autori nisu deklarirali sukob interesa relevantan za ovaj rad.

INFORMACIJA O FINANCIRANJU

Za ovaj članak nisu primljena financijska sredstva.

DOPRINOS AUTORA

Koncepcija ili nacrt rada: ŽR, DM, DR, ŠM, AR, IK, VŠ, LT

Prikupljanje, analiza i interpretacija podataka: ŽR, DR, AR, LBZ, VŠ

Pisanje prve verzije rada: ŽR, DR, VŠ

Kritička revizija: ŽR, DM, DR, ŠM, SCV, IK, LBZ, LĐ, VŠ, LT

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Table 1. Recommendations of professional societies on the determination of lipoprotein(a)

2018 American College of Cardiology / American Heart Association Cholesterol Guidelines (8)

Kada ASKVB nije objašnjena glavnim općepriznatim čimbenicima rizika (povećani LDL-kolesterol, aterijska hipertenzija, pušenje...)/ in cases where ASCVD is not explained by the major generally recognized risk factors (elevated LDL-C level, arterial hypertension, cigarette smoking…)

Kada postoji obiteljska anamneza preuranjene ASKVB / in cases with a family history of premature ASCVD

Kada su razine Lp(a) veće od 125 nmol/L (~50 mg/dL) – to se smatra čimbenikom povećanog rizika za ASKVB / in cases with Lp(a) ≥125 nmol/L (~50 mg/dL) — considered a risk-enhancing factor for ASCVD

2019 National Lipid Association Scientific Statement (9)

Osobna ili obiteljska anamneza prerane ASKVB / a personal or family history of premature ASCVD

Osobna ili obiteljska anamneza izrazite hiperkolesterolemije (LDL-kolesterol >190 mg/dL ili >4,9 mmol/L) ili sumnja na porodičnu hiperkolesterolemiju / a personal or family history of primary severe hypercholesterolemia (LDL-C >190 mg/dL or >4.9 mmol/L) or suspected familial hypercholesterolemia (FH)

Obiteljska anamneza povišenog Lp(a) / a family history of elevated Lp(a)

Granični (5% do 7,4%) i srednji (7,5% do 19,9%) 10-godišnji rizik od ASKVB (kod kojih valja razmotriti liječenje statinima) / borderline (5%–7.4%) and intermediate (7.5%–19.9%) 10-year ASCVD risk (the initiation of statin therapy to be considered in these cases)

U bolesnika s vrlo visokim rizikom za ASKVB (kod kojih valja razmotriti liječenje inhibitorima PCSK9)b/ individuals at very-high-risk of ASCVD (the initiation of PCSK9 inhibitor therapy to be considered in these cases)b

Djelomičan odgovor na terapiju za snižavanje LDL-kolesterola / partial response to LDL-C lowering therapy

Rekurentna ili progresivna ASKVB, unatoč optimalnoj terapiji za snižavanje kolesterola/ recurrent or progressive ASCVD, despite optimal lipid-lowering therapy

Kalcificirana stenoza aortne valvule / calcific aortic valve stenosis

Razine Lp(a) od 100 nmol/L (~50 mg/dL) smatraju se čimbenikom povećanog rizika za ASKVB/ Lp(a) ≥100 nmol/L (~50 mg/dL) considered a risk-enhancing factor for ASCVD

2019 European Society of Cardiology / European Atherosclerosis Society Guidelines for the Management of Dyslipidaemias (2)

Izmjeriti barem jednom u životu koncentraciju Lp(a) svake odrasle osobe/ Lp(a) measurement should be considered at least once in each adult person’s lifetime

Razine Lp(a) >430 nmol/L (>180 mg/dL) smatraju se vrlo visokim rizikom za ASKVB/ Lp(a) >430 nmol/L (>180 mg/dL) considered as very high risk for ASCVD

2019 HEART UK Consensus Statement (10)

Osobna ili obiteljska anamneza preuranjene ASKVB / a personal or family history of premature ASCVD

Srodnici u prvom koljenu s razinama Lp(a) u serumu >200 nmol/L / first-degree relatives who have Lp(a) levels >200 nmol/L

Porodična hiperkolesterolemija ili druge genske dislipidemije / familial hypercholesterolemia or other types of genetic dyslipidemia

Kalcificirana stenoza aortne valvule / calcific aortic valve stenosis

Granično povećan (ali <15%) 10-godišnji rizik za ASKVB / borderline increased (but <15%) 10-year risk of ASCVD

Razine Lp(a) >90 nmol/L smatraju se visokim rizikom za ASKVB / Lp(a) >90 nmol/L considered as high risk for ASCVD

2020 Endocrine Society Lipid Management Guidelines (11)

Obiteljska anamneza preuranjene ASKVB ili visokog Lp(a) / a family history of premature ASCVD or high Lp(a)

Osobna anamneza ASKVB-a / a personal history of ASCVD

Razine Lp(a) >125 nmol/L (~50 mg/dL) smatraju se čimbenikom povećanog rizika za ASKVB/ Lp(a) >125 nmol/L (~50 mg/dL) considered a risk-enhancing factor for ASCVD

2021 Canadian Guidelines for the Management of Dyslipidemia (12)

Izmjerite barem jednom u životu koncentraciju Lp(a) svake odrasle osobe (univerzalni probir)/ Lp(a) measurement should be done at least once in each adult person’s lifetime (universal screening)

Razine Lp(a) >100 nmol/L (~50 mg/dL) smatraju se visokim rizikom za ASKVB/ Lp(a) >100 nmol/L (~50 mg/dL) considered as high risk for ASCVD

2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement (13)

Lp(a) treba izmjeriti barem jednom kod odraslih kako bi se otkrili oni s visokim kardiovaskularnim rizikom. / Lp(a) should be measured at least once in adults to identify those with high cardiovascular risk.

Kod ishemijskog moždanog udara ili osoba s obiteljskom anamnezom preuranjene ASKVB-a ili visokog Lp(a) i bez drugih prepoznatljivih čimbenika rizika, preporučuje se načiniti probir u mladosti. / Screening is also recommended in youth with a history of ischaemic stroke or a family history of premature ASCVD or high Lp(a) and no other identifiable risk factors.

Kaskadno testiranje na povišeni Lp(a) preporučuje se kod porodične hiperkolesterolemije, kod obiteljske anamneze (vrlo) visokog Lp(a) i osobne ili obiteljske anamneze ASKVB-a. / Cascade testing for high Lp(a) is recommended in the settings of familial hypercholesterolemia (FH), family history of (very) high Lp(a), and personal or family history of ASCVD.

Laboratoriji bi trebali koristiti test za određivanje Lp(a) koji je neosjetljiv na apo(a) izoforme i u skladu s preporukama. / Laboratories should use an Lp(a) assay that is insensitive to apo(a) isoform and traceable to official reference materials.

Mjerenje Lp(a) treba biti u molarnim jedinicama ako je dostupno. Ako ne, trebale bi se koristiti jedinice u kojima je test kalibriran. / Measurement of Lp(a) should be in molar units if available. If not, the units in which the assay is calibrated should be used for reporting.

Umjesto apsolutnih vrijednosti, kliničke smjernice trebale bi razmotriti upotrebu pragova rizika sa „sivim“ zonama (npr. 30–50 mg/dL ili 75–125 nmol/L) koji bi ili uključivali (≥50 mg/dL; ~125 nmol/L) ili isključivali (<30 mg/dL; ~75 nmol/L) povećani kardiovaskularni rizik. / Rather than absolute values, clinical guidelines should consider using risk thresholds with ‘grey’ zones (e.g., 30–50 mg/dL or 75–125 nmol/L) to either rule-in (≥50 mg/dL; ~125 nmol/L) or rule-out (<30 mg/dL; ~75 nmol/L) cardiovascular risk.

Povišeni Lp(a) je čimbenik rizika čak i pri vrlo niskoj koncentraciji LDL-kolesterola. / Elevated Lp(a) is a risk factor even at very low LDL-C concentration.

Rizik od ishemijskog moždanog udara i zatajivanja srca povećava se s višim vrijednostima Lp(a) od onih povezanih s rizikom od infarkta miokarda i stenoze aortne valvule. / The risk of ischaemic stroke and heart failure increases at higher Lp(a) levels than those associated with the risk of myocardial infarction and aortic valve stenosis (AVS).

U djece je Lp(a) >30 mg/dL (>75 nmol/L) povezan s povećanim rizikom od (ponavljajućeg) ishemijskog moždanog udara. / In children, an Lp(a) >30 mg/dL (>75 nmol/L) is associated with increased risk of (recurrent) arterial ischaemic stroke.

Lp(a) nije čimbenik rizika za vensku tromboemboliju. / Lp(a) is not a risk factor for venous thromboembolism.

U nedostatku specifičnih lijekova za snižavanje povišenog Lp(a), preporučuje se rana regulacija ostalih čimbenika rizika za ASKVB osobama s povišenim Lp(a), uzimajući u obzir njihov apsolutni ukupni kardiovaskularni rizik i razinu Lp(a). / In the absence of specific Lp(a)-lowering therapies, early risk factor management is recommended for individuals with elevated Lp(a), taking into account their absolute global cardiovascular risk and Lp(a) level.

Među bolesnicima s visokim vrijednostima Lp(a) svi čimbenici kardiovaskularnog rizika trebali bi se sveobuhvatno rješavati sukladno preporukama smjernica. / Among patients with high Lp(a), all cardiovascular risk factors should be comprehensively addressed as per guideline recommendations.

Afereza lipoproteina može se rabiti kao metoda liječenja u bolesnika s vrlo visokim Lp(a) i progresivnom ASKVB koja postoji unatoč optimalnom upravljanju čimbenicima rizika. / Lipoprotein apheresis can be considered in patients with very high Lp(a) and progressive cardiovascular disease despite optimal management of risk factors.

Niacin se ne preporučuje za snižavanje Lp(a). / Niacin is not recommended for Lp(a) lowering.

Kratice / Abbrevitiaons: ASKVB, aterosklerotska kardiovaskularna bolest / atherosclerotic cardiovascular disease; Lp(a), lipoprotein(a)

a Mlađi od 55 godina kod muškaraca i mlađi od 65 godina kod žena / Younger than 55 years (men) and younger than 65 years (women); b Pojedinci s više velikih događaja ASKVB-a ili jednim velikim događajem ASKVB-a i višestruka stanja visokog rizika / Subjects with more major atherosclerotic cardiovascular disease events or one event and more high risk factors; c Mlađi od 60 godina / Younger than 60 years

Table 2. Non-genetic influences on lipoprotein(a) concentration

Stanje/Intervencija / Condition/interventionUtjecaj na vrijednost Lp(a) / Effect on Lp(a)
Način života / Lifestyle
Zamjena zasićenih masnih kiselina s ugljikohidratima i nezasićenim masnim kiselinama / Replacement of dietary saturated fat with carbohydrate or unsaturated fatPovećanje za oko 10 – 15% / Increase by about 10-15%
Dijeta s niskim udjelom ugljikohidrata i zasićenim masnim kiselinama / Low carbohydrate diet high in saturated fatSmanjenje za oko 15% / Decrease by about 15%
Post / FastingNikakav / None
Fizička aktivnost / Physical activityNikakav/minimalan / None/minimal
Hormoni i s hormonskim poremećajima povezana stanja / Hormones and related conditions
Hipertireoza / HyperthyroidismSmanjenje; 20 – 25% povećanje s tireostaticima ili terapijom radioaktivnim jodom / Decrease; 20-25% increase with thyrostatic treatment or radioactive iodine therapy
Hipotireoza / Hypothyroidism

Povećanje; 5 – 20% smanjenje uz nadomjesnu terapiju

/ Increase; 5-20% decrease with replacement therapy

Hormoni rasta / Growth hormonesDvostruko povećanje uz terapiju / Double increase with therapy
Endogeni spolni hormoni / Endogenous sex hormonesNikakav/minimalan / None/minimal
Trudnoća / PregnancyDvostruko povećanje / Double increase
Menopauza / MenopauseNikakav/minimalan / None/minimal

Postmenopauzalana hormonska nadomjesna terapija

/ Postmenopausal hormone replacement therapy

Smanjenje za oko 25% / About 25% decrease

Kirurška ili biokemijska kastracija u muškaraca

/ Surgical or biochemical castration in men

Malo povećanje / Small increase

Ovarijektomija, antagonisti estrogenskih receptora

/ Ovariectomy, oestrogen receptor antagonist

Malo povećanje / Small increase
Kronične bubrežne bolesti / Chronic kidney disease
Nefrotski sindrom / Nephrotic syndromePovećanje za 3 – 5 puta (u odnosu na kontrole) / 3–5× increase (vs. control)

Bolesnici na peritonejskoj dijalizi

/ Peritoneal dialysis patients

Dvostruko povećanje (u odnosu na kontrole) / Double increase (vs. control)

Liječenje hemodijalizom i kronična bubrežna bolest

/ Haemodialysis treatment and chronic kidney disease

Porast čestica s velikim apo(a) izoformama

/ Increase in large apo(a) isoform carriers

Transplantacija bubrega / Kidney transplantationNormalizacija vrijednosti / Normalization of levels
Oštećenje jetre / Liver impairmentSmanjenje ovisno o uzroku / Decrease, depending on cause
Transplantacija jetre / Liver transplantationPromjene izoforme apo(a) u odnosu na izoformu donora, s odgovarajućim promjenama u razinama Lp(a) / Changes of apo(a) isoform in relation to isoform of the donor, with corresponding changes in Lp(a) levels
Upala i povezana stanja / Inflammation and related conditions

Teška, po život opasna akutna stanja (sepsa, opekline)

/ Severe, life-threatening acute-phase conditions (sepsis, severe burns)

Smanjenje / Decrease
Neka upalna stanja / Some inflammatory conditionsPovećanje / Increase

Tocilizumab (inhibitor interleukina-6)

/ Tocilizumab (inteleukin-6-inhibitor)

~30 – 40% smanjenje / Decrease by about 30-40%

Inhibitori proteaze, antiretrovirusna terapija

/ Protease inhibitors, antiretroviral therapy

Povećanje / Increase
Statini / StatinsMogu blago povećati vrijednosti Lp(a) / May slightly increase Lp(a)

Zagađenje zraka (fine čestice, PM2,5)

/ Air pollution (fine particulate matter, PM2.5)

Blago povećanje / Slight increase

Tablica prilagođena prema / Table adapted from: Kronenberg F, et al. / et al. Eur Heart J. 2022;43:3925–3946.

Figure 1. Risk of clinical outcomes with Lp(a) concentration Apsolutni i relativni rizici od stenoze aortnog zaliska, ishemijskog moždanog udara, infarkta miokarda i zatajivanja srca u općoj populaciji kao funkcija povećanja koncentracije Lp(a) u plazmi. Gornji grafikon prikazuje apsolutni rizik na 10.000 osoba-godina, a donji grafikoni prikazuju omjere rizika kao punu crvenu liniju s 95% intervalima pouzdanosti prikazanim kao isprekidane crne linije; kada niži interval pouzdanosti od 95% više ne preklapa referentnu vrijednost omjera rizika od 1,0 za srednju koncentraciju Lp(a) rizik je značajno povišen. Na temelju podataka 70.286 bijelaca iz općega populacijskog ispitivanja provedenog u Kopenhagenu s medijanom praćenja od 7,4 godine. / Absolute and relative risks of aortic valve stenosis, ischemic stroke, myocardial infarction and heart failure in general population as a function of increased Lp(a) plasma concentration. Top figure shows the absolute risk per 10 000 person/years, and lower figures show hazard ratios as solid red line, with 95% confidence intervals as dotted black lines;when the lower 95% confidence interval no longer overlaps the hazard ratios reference values of 1.0 for the median Lp(a) plasma concentration, risk is significantly increased. Data are based on 70 286 white subjects in the Copenhagen General Population Study with a median 7.4 years of follow-up. Prilagođeno prema / Adapted from: Kronenberg F, et al. / et al. Eur Heart J. 2022;43:3925–46.

Table 3. Summary of epidemiological and genetic evidence for the association of lipoprotein(a) concentration with clinical outcomes

Ispitivanje parova ili presječno ispitivanje

/ Case control or cross-sectional studies

Velika prospektivna opservacijska ispitivanja

/ Large prospective observational studies

Metaanalize velikih prospektivnih opservacijskih ispitivanja

/ Meta-analyses of prospective observational studies

Velika svegenomska ispitivanja asocijacije

/ Large genome-wide association studies

Velika mendelijanska randomizacijska ispitivanja

/ Large Mendelian randomization studies

Klinička ispitivanja liječenja za snižavanje Lp(a)

/ Clinical trials of Lp(a)-lowering therapy

Infarkt miokarda / Myocardial infarction (15–21)Da / YesDa / YesDa / YesDa / YesDa / Yes

Ispitivanje u tijeku

/ Trial ongoing

Angina pektoris/koronarna stenoza

/ Angina pectoris/coronary stenosis (22–24)

Da / YesDa / Yes

Nedostaje podataka

/ Data lacking

Da / YesDa / Yes–

Ishemijski moždani udar

/ Ischemic stroke (16, 18, 20, 22, 25–30)

Da / YesDa / YesDa / YesDa / YesDa / Yes

Ispitivanje u tijeku

/ Trial ongoing

Stenoza karotida

/ Carotid stenosis (22, 23, 31, 32)

Da / YesDa / Yes

Nedostaje podataka

/ Data lacking

Da / YesDa / Yes–

Periferna arterijska bolest

/ Peripheral arterial disease (20, 22, 23, 33–35)

Da / YesDa / Yes

Nedostaje podataka

/ Data lacking

Da / YesDa / Yes–

Stenoza aortnog zaliska

/ Aortic valve stenosis (16, 36–45)

Da / YesDa / Yes

Nedostaje podataka

/ Data lacking

Da / YesDa / Yes–

Zatajivanje srca

/ Heart failure (16, 44)

Da / YesDa / Yes

Nedostaje podataka

/ Data lacking

Da / YesDa / Yes–

Kardiovaskularna smrtnost

/ Cardiovascular mortality (16, 20, 25, 46–48)

Da / YesDa / Yes

Nedostaje podataka

/ Data lacking

Da / YesDa / Yes

Ispitivanje u tijeku

/ Trial ongoing

Smrt od svih uzroka

/ All-cause mortality (25, 47, 49, 50)

Nedostaje podataka

/ Data lacking

Da / YesNe / NoDa / YesDa / Yes

Ispitivanje u tijeku

/ Trial ongoing

Venska tromboembolija

/ Venous thromboembolism (22, 51, 52)

Ne / NoNe / NoNe / NoNe / NoNe / No–

Da/Yes = opisana povezanost između Lp(a) i ishoda / association between Lp(a) and outcome has been described; Ne/No = nema izviještene povezanosti između Lp(a) i ishoda / no association between Lp(a) and outcome has been noted; Nedostaje podataka / Data lacking – znači da ispitivanja nisu dostupna / means that tests are not available. Tablica prilagođena prema / Table adapted from: Kronenberg F, et al. / et al. Eur Heart J. 2022;43:3925–46.

Table 4. More significant studies on the possibilities of certain therapies in lowering elevated lipoprotein(a) [Lp(a)]

Izvor / Source

Dizajn

/ Design

Populacija / PopulationIshodi / Outcomes
Statini / Statins

Willeit, et al.

/ et al., 2018 (17)

Metaanaliza

/ Meta-analysis

29.069 bolesnika s dokazanom kardiovaskularnom bolesti s terapijom statinima ili bez nje / 29 069 patients with proven cardiovascular disease with or without statin treatment

Statini snižavaju koncentracije LDL-kol. bez značajnog utjecaja na razine Lp(a)

/ Statins decrease LDL-cholestrol concentrations without any significant effect on Lp(a) levels

Tsimikas, et al.

/ et al., 2020 (71)

Metaanaliza

/ Meta-analysis

5.256 bolesnika (1.371 na placebu i 3.885 na različitim statinima) iz 6 kliničkih ispitivanja / 5256 patients (1371 on placebo and 3885 on different statins) from 6 clinical trials

Prosječne promjene koncentracije Lp(a) od početnih vrijednosti kretale su se od 8,5% do 19,6% u statinskoj skupini

/ Average changes in Lp(a) concentrations from starting values were 8.5-19.6% in statin group

PCSK9 inhibitori / PCSK9 inhibitors
Fourier (64)

Kliničko ispitivanje

/ Clinical trial

25.096 bolesnika s ASKVB-om na intenzivnoj terapiji statinima s ezetimibom ili bez njega / 25 096 patients with atherosclerotic cardiovascular disease on intensive statin treatment with or without ezetimibe

Evolokumab snižava Lp(a) prosječno za

26,9% u odnosu na početne vrijednosti u 48 tjednu i za 23% smanjuje rizik velikih KV događaja u bolesnika s početnim vrijednostima Lp(a) iznad 37 nmol/L

u usporedbi s placebom / Evolocumab decreases Lp(a) on average by 26.9% when compared with starting values in 48th week, and decreases risk of major cardiovascular events by 23% in patients with starting Lp(a) values above 37 nmol/L when compared with placebo

Odyssey

outcomes (65)

Kliničko ispitivanje

/ Clinical trial

18.924 bolesnika koji su imali AKS i koji su bili na intenzivnoj terapiji statinima / 18 924 patients with acute coronary syndrome on intensive statin treatment

Alirokumab snižava Lp(a) u prosjeku za

23% od početnih vrijednosti u 4. mjesecu; više početne vrijednosti Lp(a) su bile povezane s jačim sniženjem Lp(a),

što je bilo povezano sa značajnim smanjenjem rizika za velike KV događaje neovisno o razinama LDL-kolesterola

/ Alirocumab decreases Lp(a) on average by 23% from starting values in 4th month; higher starting Lp(a) values were associated with greater Lp(a) decrease which was associated with significant decrease of risk for major cardiovascular events independently of LDL-cholesterol levels

RNK terapije / RNA therapies
miRNK
ORION 9, 10 i 11 (66, 67)

Klinička ispitivanja

/ Clinical trials

3.660 bolesnika. Istraživanje djelotvornosti i sigurnosti inklisirana tijekom 18 mjeseci, u bolesnika s heterozigotnom porodičnom hiperkolesterolemijom, ASKVB ili ekvivalent rizika za ASKVB / 3660 patients. Investigation of efficacy and safety of inclirisan during 18 months in patients with heterozygous familial hypercholesterolemia, ASCVB or risk equivalent for ASCVB

Inklisiran je prosječno snizio vrijednosti Lp(a) u nmol/L 540. dana između 17% do 26% kao mjera sekundarnog ishoda.

/ Inclisiran decreased Lp(a) on average by 17-26% after 540 days as a measure of secondary outcome.

Olpasiran

(AMG 890) (72)

Faza 1

/ Phase 1

64 zdrava odrasla sudionika s Lp(a) ≥70 nmol/L

/ 64 healthy adult persons with Lp(a) ≥70 nmol/L

Olpasiran je ovisno o dozi prosječno snizio Lp(a) za 71% do 97% od početne vrijednosti ≥70 do ≤199 nmol/L, a u bolesnika koji su imali Lp(a) ≥200 nmol/L za 76% do 91%.

/ Olpasiran decreased Lp(a) dose dependently on average by 71-97% from starting values ≥70 to ≤199 nmol/L, and in patients with Lp(a) ≥200 nmol/L by 76-91%.

ASO
APO(a)Rx (73)

Faza 2

/ Phase 2

64 zdrava sudionika s Lp(a) ≥125 nmol/L / 64 healthy persons with Lp(a) ≥125 nmol/L

APO(a)Rx je značajno snizio Lp(a) nakon 85 dana za 70%

/ APO(a)Rx significantly decreased Lp(a) after 85 days by 70%

Pelacarsen

(TQJ230) (73)

Faza 1/2a

/ Phase 1/2a

58 zdrava sudionika s Lp(a)

≥75 nmol/L

/ 58 healthy persons with Lp(a)

≥75 nmol/L

Pelakarsen je značajno prosječno snizio ovisno o dozi Lp(a). Sniženje je bilo do 92% kod najveće doze, ali je bilo značajno i kod svih manjih pojedinačnih i višestrukih doziranja nakon 30 i 36 dana. / Pelacarsen significantly decreased Lp(a) dose dependently. The highest dose decreased Lp(a) up to 92% but lower doses decreased it also significantly after 30-36 days.

Pelacarsen

(TQJ230) (74)

Faza 2

/ Phase 2

286 bolesnika s dokazanom KVB i početnim Lp(a) ≥150 nmol/L

/ 286 patients with proven cardiovascular disease and Lp(a)

≥150 nmol/L at the beginning

Pelakarsen je značajno, ovisno o dozi prosječno snizio Lp(a) i do 80% nakon 6 mjeseci u odnosu na početne vrijednosti. / Pelacarsen decreased Lp(a) significantly dose dependently up to 80% after 6 months when compared with starting values.

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Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, et al. AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382(3):244–255. PubMed https://doi.org/10.1056/NEJMoa1905239</jrn> Table 1. Recommendations of professional societies on the determination of lipoprotein(a).

 

| 2019National Lipid Association Scientific Statement (9) |.

Acknowledgements

Zahvala prof. dr. sc. Kristini Selthofer-Relatić za intelektualnu pomoć prigodom izrade članka.

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