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Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD) and Lp(a) is acknowledged as a risk factor to be included in risk assessment. The established lipid-modifying medical therapies do not lower Lp(a) except niacin but no data of endpoint trials are available. Of the new lipid-modifying drugs a few have some impact on Lp(a). Whether the Lp(a) lowering effect contributes to the reduction of CVD events would have to be shown in Lp(a) dedicated trials. None of the available agents is indicated to lower Lp(a). Lipoprotein apheresis lowers levels of Lp(a) signiﬁcantly by >60% per treatment. Trial data and data of the German Lipoprotein Apheresis Registry show that regular apheresis reduces cardiovascular events. The Apo(a) antisense oligonucleotide is the only approach to speciﬁcally lower Lp(a). The IONIS-APO(a) phase 1 and 2 trials showed very substantial decreases of Lp(a) and good Rx tolerability. The hepatospeciﬁc variant IONIS-APO(a)-L is 30 times more potent. The results of the IONIS-APO(a)-L Rx Rx phase 2 trial were presented recently. The highest dosages reduced Lp(a) by 72 and 80%; in about 81 and 98% Lp(a) levels <50 mg/dl were achieved. Tolerability and safety were conﬁrmed, whereby injection site reactions were the most common side effects. This raises hope that the planned phase 3 trial will reproduce these ﬁndings and show a reduction of cardiovascular events. Keywords LDL-Cholesterol · Lipid lowering therapy · Antisense oligonucleotides · Atherosclerosis · Cardiovascular disease Introduction rosis Society/European Society of Cardiology (EAS/ESC) Guidelines  and are considered to be a risk-enhancing In 1963 Berg described the lipoprotein(a) (Lp(a)) system factor by the 2018 American Heart Association/American in man, was the ﬁrst to note that the individual level of College of Cardiology (AHA/ACC) Guideline . The Lp(a) is inherited and that high levels are associated with consensus paper of the European Atherosclerosis Society early onset of atherosclerosis . In the following decades gives a comprehensive overview of Lp(a) as a cardiovascu- epidemiological data supported the initial ﬁndings, genetic lar risk factor . The authors suggest measuring Lp(a) trials conﬁrmed that Lp(a) is a causal factor for develop- in individuals at intermediate or high risk of CVD, in case ing atherosclerosis, and the negative impact of high levels of premature CVD, familial hypercholesterolaemia, family of Lp(a) not only on coronary heart disease but also on history of premature CVD or high Lp(a), progressive CVD development of aortic stenosis, peripheral arterial disease, despite statin therapy, ≥3% 10-year risk of fatal CVD (Eu- and ischaemic stroke was shown [2–12]. On the other hand ropean SCORE), or ≥10% 10-year risk of fatal or non-fatal much is still almost unknown, e. g. the physiological role of coronary heart disease (US guidelines). Lowering LDL-c Lp(a), the catabolism, and the clinical relevance in throm- remains the ﬁrst priority. Secondary a Lp(a) level <50 mg/dl botic and embolic events. High levels of Lp(a) are acknowl- (~ <80th percentile) is suggested as desirable. The some- edged as being associated with an increased risk of cardio- what arbitrary cut off level of 30 mg/dl is often used based vascular disease (CVD) by the 2016 European Atheroscle- on data showing the continuous increase of risk with in- creasing levels of Lp(a) and without an obvious threshold value . Since no endpoint data are available no target This article is part of the special issue “Lp(a) – Update 2018” level can be speciﬁed. Anja Vogt Anja.Vogt@med.uni-muenchen.de Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336 Munich, Germany K 52 A. Vogt Treatment options the target or a primary endpoint. Since all agents primarily lower LDL-c it would be difﬁcult to show if the Lp(a) lower- For statins, the backbone treatment for preventing and re- ing effect is clinically relevant, as with niacin. Of these, only ducing cardiovascular events by lowering LDL-c, small de- PCSK9 inhibitors are widely available. Both evolocumab creases or increases of Lp(a) have been shown . But and alirocumab lower LDL-c about 50 to 60% and in some mostly Lp(a) is not affected by statins [15, 17, 18]. The trials the lowering of Lp(a) was assessed, too. The mecha- same is seen for ezetimibe . nism by which Lp(a) is reduced is matter of debate. With Nicotinic acid (niacin) has a broad range of lipid-mod- evolocumab reductions of 25.5%  and with alirocumab ifying effects, lowering LDL-c and triglycerides and in- reductions of 30.2%  were reported. A pooled anal- creasing high density lipoprotein-cholesterol (HDL-c). In ysis  of three phase 2 trials using alirocumab for 8 or addition it was shown to lower Lp(a) for the ﬁrst time in 12 weeks analysed the Lp(a) lowering effect. Levels ranged 1989 . High doses of nicotinic acid (2000–4000 mg) from 2 to 181 mg/dl and the two groups consisted of par- are needed to reduce Lp(a) signiﬁcantly . However, ticipants with baseline levels of 50 mg/dl and ≥50 mg/dl. this effect has not yet been shown in patients with high The median absolute reduction was 3.5 and 27 mg/dl, re- baseline levels of Lp(a) with regard to the inclusion crite- spectively, the median percent reduction 36 and 27%, re- rion. A meta-analysis has summarised the beneﬁcial effects spectively. Interestingly in patients with LDL-receptor neg- of nicotinic acid on cardiovascular events , but it was ative homozygous FH evolocumab reduced Lp(a) by 20% not evaluated if the beneﬁt is attributable to reduced lev- while LDL-c did not decrease . The upregulation of els of Lp(a). Additionally the positive effects are mainly other receptors, e. g. the very low density (VLDL) recep- from the pre-statin era. The EAS consensus paper states tor that mediates the uptake of Lp(a) into macrophages, that niacin should be used to reduce high levels of Lp(a) might be an explanation for this ﬁnding. There are further because of the evidence and despite the fact that it cannot contradictory results by what mechanism Lp(a) is reduced. be excluded that the beneﬁts are not attributed to lower- Some data show an increased catabolic fraction rate, oth- ing Lp(a) but to the favorable effects on other lipoproteins ers a reduced synthesis . In the FOURIER trial Lp(a) . In 2013 the combination of extended release niacin was reduced signiﬁcantly by evolocumab and participants and laropiprant, a ﬂush inhibitor, was withdrawn from the with higher absolute reductions of Lp(a) tended towards a European market after the Heart Protection Study 2—Treat- greater beneﬁt . ment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) was stopped early because of a signiﬁcant Antisense oligonucleotides increase in bleeding events, including intracranial haemor- rhage . Although the reasons have not been elucidated the use of nicotinic acid continues to be debated. Antisense oligonucleotide (ASO) drugs are a relatively new Lipoprotein apheresis (LA) as an extracorporeal method way to very speciﬁcally target genes on the mRNA level and lowers LDL-c and Lp(a) acutely and signiﬁcantly by are used in different medical ﬁelds. Mipomersen, the ﬁrst 60–70% but has to be applied regularly (mostly weekly). ASO used in hypercholesterolaemia, interferes with the en- Few countries consider high levels of Lp(a) to be an indi- coding mRNA for ApoB100. The production of ApoB100 cation for lipoprotein apheresis in very high-risk patients is reduced via inhibition of translation to the protein. Con- if all other cardiovascular risk factors, mainly LDL-c, are sequently less very low density lipoprotein (VLDL) is as- treated optimally [24–27]. sembled in the liver resulting in lower levels of circulat- Beneﬁcial effects of LA on the course of CVD are shown ing LDL-c. As a side effect, less triglycerides are excreted by retrospective evaluations, prospective (but not blinded, from the liver and accumulate often leading to fatty liver randomized controlled) trials, and analyses of the German disease and elevated transaminases [43, 44]. By what mech- Lipoprotein Apheresis Registry [28–35]. LA is generally anism levels of Lp(a) are lowered is not entirely clear. In well tolerated and safe [27, 36] but time consuming, ex- four phase 3 trials mipomersen given subcutaneously ver- pensive, only offered in specialised centres, and often not sus placebo levels of Lp(a) were signiﬁcantly reduced by covered by health insurance. 21–39% . Thus mipomersen might reduce the neces- sity for lipoprotein apheresis in high-risk patients [46, 47]. The most common side effects were severe injection site New drug developments reactions and liver steatosis is also of concern. Because of the side effects mipomersen was not widely approved and Several new lipid-modifying drugs to reduce LDL-c are is available in the USA only. currently under investigation. They lower LDL-c and Lp(a) to varying degrees though lowering of Lp(a) has never been K Lp(a)—antisense therapy 53 Apo(a) antisense oligonucleotide tion of 10, 40, 80, or 120 mg versus placebo. In the multi- ple-dose phase (n = 30) IONIS-APO(a)L 10 mg, 20 mg, or Rx IONIS-APO(a) , an antisense oligonucleotide molecule, 40 mg were administered at days 1, 3, 5, 8, 15, and 22 ver- Rx is the ﬁrst measure developed to speciﬁcally address the sus placebo. The primary efﬁcacy endpoint was reduction mRNA of Apo(a). Trials in transgenic mice  and phase 1 of Lp(a) at day 30 (single-dose phase) and day 36 (multi- results showed relevant decreases of Lp(a). In a phase 1 ple-dose phase). Baseline levels of Lp(a) were 147.8 nmol/l trial in healthy volunteers (Lp(a) levels ≥25 nmol/l) IO- (mean) and 128.6 nmol/l (median) in the single-dose phase NIS-APO(a) signiﬁcantly lowered Lp(a) in a dose-depen- and 153.8 nmol/l (mean) and 145.6 nmol/l (median) in the Rx dent manner. The highest dose of 300 mg reduced Lp(a) by multiple-dose phase. 77.8%. In one individual the maximal reduction was 88.8% In the single ascending dose phase Lp(a) was reduced after 36 days. Impressively Lp(a) did not increase imme- signiﬁcantly in a dose-dependent manner at day 30. The diately but was still low 84 days after the last application mean treatment differences versus placebo (+2.8%) were . Theuse was safeand themostcommon sideeffects 24.8% (10 mg group), 35.1% (20 mg group), 48.2% (40 mg were injection site reactions. As a ligand-conjugated variant group), 82.5% (80 mg group), and 84.5% (120 mg group). of IONIS-APO(a) the hepatocyte speciﬁc IONIS-APO(a)- The reduction was still signiﬁcant after 90 days (46% in Rx L was developed. The triantennary N-acetylgalactosamine the 80 mg group and 44% in the 120 mg group). Also Rx complex (GalNAc ) facilitates the fast and speciﬁc uptake in the multiple ascending dose phase Lp(a) was reduced by hepatocytes . This modiﬁcation enhanced the po- signiﬁcantly. The treatment differences versus placebo tency of the Apo(a)-ASO by >30 times . Since Apo(a) were 59.4% (10 mg group), 72.3 (20 mg group), and 82.4% is targeted VLDL is produced and there is no fat accumu- (40 mg group). At day 113 after the last application the low- lation in the liver. ering effect was still signiﬁcant with 39% (10 mg group), The IONIS-APO(a) phase 2 trial conﬁrmed the positive 53% (20 mg group), and 58% (40 mg group). Rx results regarding effectivity and safety . In 64 partic- The results of the biggest conducted IONIS-APO(a)-L Rx ipants IONIS-APO(a) was applied subcutaneously in an (AKCEA-APO(a)-L ) phase 2 trial were presented at the Rx Rx escalating-dose manner for 12 weeks (100 mg, 200 mg, and AHA Scientiﬁc Sessions, Late-Breaking Clinical Trial Pre- 300 mg, each once a week for 4 weeks) versus placebo. sentation, on 10 November 2018 . The trial was a ran- Two cohorts were formed according to Lp(a) baseline domized, double-blind, placebo-controlled, and dose-rang- levels: cohort A: Lp(a) 125–437 nmol/l (placebo group: ing trial in 286 patients with established CVD and high mean 251.6 nmol/l and median 216.3 nmol/l, verum group: levels of Lp(a) (baseline mean of approximately 100 mg/dl mean 254 nmol/l, median 261.4 nmol/l) and cohort B: Lp(a) [250 nmol/l]). Five cohorts were compared: 20 mg were ad- ≥438 nmol/l (placebo group: mean 488.3 nmol/l and me- ministered every 4 weeks, 40 mg every 4 weeks, 20 mg ev- dian 498.3 nmol/l, verum group: mean 444.9 nmol/l, median ery 2 weeks, 60 mg every 4 weeks, and 20 mg every week, 457.6 nmol/l). The primary efﬁcacy endpoint was reduction each for 6–12 months. The primary efﬁcacy endpoint was of Lp(a) at day 85 or 99. Secondary endpoints were effects percent change in Lp(a) from baseline at 6 months. on other lipoproteins and risk factors. AKCEA-APO(a)-LRx decreased Lp(a) in all groups In both cohorts Lp(a) was reduced signiﬁcantly: co- (20 mg every 4 weeks: –35%, 40 mg every 4 weeks –56%, hort A—66.8%, cohort B—71.6% at day 85/99. Addition- 20 mg every 2 weeks: –58%). The effect was even greater ally, levels of LDL-c, ApoB, and oxidised phospholipids in the highest doses (60 mg every 4 weeks: –72%, 20 mg (OxPL) were reduced signiﬁcantly in both cohorts. LDL- weekly: –80%) and in about 81% and 98%, respectively, c was lowered by 13.0% in cohort A and by 23.9% in co- Lp(a) levels <50 mg/dl were achieved. The completion rate hort B, ApoB by 11.3 and 18.5%, respectively, OxPL-ApoB was high (90%) and comparable in both groups (verum by 35.2 and 42.5%, respectively, and OxLP-Apo(a) 26.6 and 12.1%, placebo 14.9%). There were no severe safety con- 36.7%, respectively. Baseline statin therapy had no signif- cerns and few adverse events. Injection site reactions were icant effect on these results. The treatment was safe and the most common (26%) with one patient discontinuing. well tolerated. Two myocardial infarctions and one episode of angina pectoris in high-risk patients were not assessed as treatment related. Injection site reactions occurred in 10% Conclusion in cohort A and in 19% in cohort B (one participant stopped treatment). The new developments of lipid-modifying drugs will allow Another phase 1/2a ﬁrst-in-man trial  was done with a more effective reduction of LDL-c and Lp(a) and a more the GalNAc modiﬁed IONIS-APO(a)-L in healthy vol- patient-individualised therapy. LDL-c treatment goals and 3 Rx unteers with levels of Lp(a) ≥75 nmol/l. In the single-dose even lower levels than recommended by guidelines today phase participants (n = 28) received one subcutaneous injec- can be reached. The ﬁrst outcome trials show that car- K 54 A. Vogt Study. Circulation 117(2):176–184. https://doi.org/10.1161/ diovascular events are reduced as a consequence. 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Role of lipoprotein(a) and apolipoprotein(a) phenotype in athero- genesis: prospective results from the Bruneck study. Circulation Compliance with ethical guidelines 100(11):1154–1160 11. Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, Auinger M, Prib- Conﬂict of interest A. Vogt has received speakers’ honoraria for pre- asnig A, Meisl T, Konig P, Dieplinger H (1999) The low molecu- sentations and advisory board activities by Aegerion, Amgen, Berlin lar weight apo(a) phenotype is an independent predictor for coro- Chemie, Fresenius, Genzyme, a Sanoﬁ company, Kaneka, OmniaMed, nary artery disease in hemodialysis patients: a prospective follow- Regeneron, Sanoﬁ. AV has received research support by Merck Sharp up. J Am Soc Nephrol 10(5):1027–1036 & Dohme. 12. Sandholzer C, Saha N, Kark JD, Rees A, Jaross W, Dieplinger H, Hoppichler F, Boerwinkle E, Utermann G (1992) Apo(a) isoforms Ethical standards This article does not contain any studies with human predict risk for coronary heart disease. A study in six populations. participants or animals performed by any of the authors. Arterioscler Thromb 12(10):1214–1226 13. Authors/Task Force M, Piepoli MF, Hoes AW, Agewall S, Albus C, Open Access This article is distributed under the terms of the Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton Creative Commons Attribution 4.0 International License (http:// C, Graham I, Hall MS, Hobbs FD, Lochen ML, Lollgen H, Mar- creativecommons.org/licenses/by/4.0/), which permits unrestricted ques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, use, distribution, and reproduction in any medium, provided you give Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren appropriate credit to the original author(s) and the source, provide a WM, Additional Contributor: Simone B, Document R, De Backer link to the Creative Commons license, and indicate if changes were G, Rofﬁ M, Aboyans V, Bachl N, Bueno H, Carerj S, Cho L, Cox made. 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