Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘Controlled study of the effect of proprotein convertase subtilisin–kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics’†, by G.F. Watts et al., on page 2577. Lipoprotein(a) [Lp(a)] is an LDL-like particle in which apolipoprotein(a) is linked to apoB via a disulfide bond; epidemiological and genetic studies indicate that elevated plasma levels of Lp(a) are a cardiovascular risk factor independent of LDL.1 Furthermore, a strong association between elevated Lp(a) levels and calcific aortic valve stenosis has been shown, and Mendelian randomization studies have confirmed that Lp(a) is causally involved.2 Owing to the sequence homology with plasminogen, high Lp(a) levels are also believed to promote an athero-thrombotic condition via several mechanisms, including the inhibition of the fibrinolytic system and enhancement of the tissue factor-mediated pathway.3 Finally, it is now clear that elevated Lp(a) levels remain a cardiovascular risk factor even in patients with controlled LDL-cholesterol (LDL-C) levels,4 indicating that lowering Lp(a) levels should translate into a cardiovascular benefit. Lp(a) levels are genetically determined, and primarily controlled by synthesis rather than catabolism,4 and the facts that statins, despite their efficacy in reducing LDL-C levels by increasing hepatic LDL receptor (LDLR) expression, have no or little effect on Lp(a) levels,5 and that lipid-lowering drugs which act by reducing apoB synthesis or LDL assembly (including mipomersen and lomitapide) reduce Lp(a) levels6 was somehow in line with expectations. It has therefore become quite puzzling that PCSK9 (proprotein convertase subtilisin–kexin type 9) inhibitors, which also act by increasing LDLR expression, significantly reduce Lp(a) levels by up to 30%.7,8 Kinetic studies are believed to be the gold standard in understanding whether a pharmacological intervention modifies the rate of synthesis or catabolism of a given protein, and this approach has successfully elucidated in vivo the mechanisms by which statins and other drugs affecting plasma lipoproteins act.9,10 One of the complexities with lipoproteins is that the main protein of LDL, apoB, is mostly released in the circulation in VLDL and then eventually, by several remodelling passages, becomes an LDL; interpretation of the data via modelling of the kinetics is a must, with multiple compartments to fit the kinetic curves. A second level of complexity relates to Lp(a) owing to the fact that the lipoprotein is assembled by associating with an LDL, making kinetic studies even more complex. In the present issue of the journal, Watts and colleagues have investigated by kinetic studies the mechanisms by which evolocumab (a PCSK9 inhibitor) reduces Lp(a) levels.11 They confirmed that treatment with atorvastatin alone did not affect Lp(a) levels, with no changes in the fractional catabolic rate (FCR) or the production rate of Lp(a)–apo(a). Treatment with evolocumab or evolocumab + atorvastatin resulted in comparable reductions of Lp(a) levels (–33% and –38%, respectively).11 However, such reductions were achieved through two different mechanisms: when administered as monotherapy, evolocumab reduced the production rate of Lp(a)–apo(a) without affecting its FCR.11 In contrast, when given in combination with atorvastatin, the FCR of Lp(a)–apo(a) significantly increased, without alterations of its production rate.11 A previous study in which alirocumab was tested vs. placebo reported different results: inhibition of PCSK9 reduced plasma Lp(a) levels by 18.7% (P < 0.01), and this reduction was associated with a trend for an increase in the median FCR of Lp(a)–apo(a) (24.6%; P = 0.09) and no changes in its production rate.12 The reason for this discrepancy is unclear; it should be noted that the degree of Lp(a) reduction in this study was somewhat less.12 Differences in the baseline characteristics of subjects taking part in these two studies, including differences in Lp(a) baseline levels, age, body mass index (BMI), and ethnicity,11,12 may contribute to explaining these differences. Apo(a) isoform size may also play a role, as it may influence both production and catabolism of Lp(a) particles.13 In vitro, both LDL and Lp(a) compete with LDL for the binding to the LDLR, but higher concentrations of the latter are required, suggesting that the two lipoproteins have different affinities for the LDLR, that of LDL being higher. Thus, it can be assumed that when LDL-C levels are massively reduced, Lp(a) clearance can increase due to a higher availability of ‘free’ LDLR. Statin-induced inhibition of intracellular cholesterol synthesis by inducing the activation of SREBP-2 up-regulates the expression of both the LDLR and PCSK9, and the expression of the LDLR might not be high enough to support direct Lp(a) removal. By analogy, in the presence of PCSK9 inhibitors, circulating PCSK9 is reduced, leading to a higher availability of LDLR for LDL internalization, which again may not be enough to remove Lp(a) particles efficiently. However, under these circumstances, evolocumab reduced Lp(a) levels by reducing the production of Lp(a).11 This observation is supported by a previous study showing that PCSK9 enhanced the secretion of Lp(a) from cultured hepatocytes, an effect that was blunted by alirocumab, without any effect on Lp(a) uptake.14 This study could not demonstrate an involvement of LDLR in the uptake of Lp(a).14 It is intriguing to suggest an intracellular role for PCSK9 in modulating Lp(a) plasma levels; the mechanism, however, has not been addressed so far. When given in combination with a statin, the concomitant increase of LDLR expression and reduction of circulating PCSK9 leads to a further increased availability of ‘free’ LDLR and to a massive decrease of LDL-C; this in turn leads to a profound reduction of the high-affinity ligand of the LDLR (i.e. LDL), thus allowing the binding of a lower affinity ligand [i.e. Lp(a)]. This finding is supported by the observation that the reduction in Lp(a) levels was significantly correlated with the reduction in LDL-C levels: there was a greater Lp(a) percentage reduction in patients who achieved LDL-C ≤40 mg/dL than in those who achieved LDL-C >70 mg/dL, supporting a relevant role for the LDLR in the removal of Lp(a).7 One way to address this possibility would be to clamp LDL levels externally to higher values and then re-perform kinetics. A reduction of the FCR should be observed. Take home figure View largeDownload slide Possible mechanisms of statins and monoclonal antibodies (mAbs) against PCSK9 on Lp(a) metabolism. The LDLR seems to be involved in Lp(a) catabolism, but other receptors may also play a role. (A) Under physiological conditions, LDLR surface expression is regulated by the content of intracellular cholesterol and the amount of extracellular PCSK9. (B) Statins reduce cholesterol biosynthesis, leading to the up-regulation of both the LDLR and PCSK9. LDL-C levels are decreased. Under this condition, the LDLR is not available for a lower affinity binding with Lp(a) as it is mainly engaged in the removal of LDL. Other receptors possibly involved in Lp(a) uptake might be controlled by PCSK9. The increased levels of PCSK9 may lead to an increased formation of PCSK9–Lp(a) (and/or LDL) complexes. (C) In the presence of anti-PCSK9 mAb, extracellular PCSK9 is sequestered; thus, LDLR is recycled to the surface and available for new binding. The reduction of PCSK9 reduces the production of Lp(a) particles through several mechanisms. Lp(a)–PCSK9 complexes may be recognized by the anti-PCSK9 mAb, promoting an alternative removal pathway. (D) In the presence of statin and mAb to PCSK9, both LDLR expression and recycling are increased, leading to a massive reduction of LDL particles. This increases the number of free LDLRs, which are thus available for low affinity binding with Lp(a), leading to an increased Lp(a) uptake. Other receptors may contribute to removal of Lp(a). Take home figure View largeDownload slide Possible mechanisms of statins and monoclonal antibodies (mAbs) against PCSK9 on Lp(a) metabolism. The LDLR seems to be involved in Lp(a) catabolism, but other receptors may also play a role. (A) Under physiological conditions, LDLR surface expression is regulated by the content of intracellular cholesterol and the amount of extracellular PCSK9. (B) Statins reduce cholesterol biosynthesis, leading to the up-regulation of both the LDLR and PCSK9. LDL-C levels are decreased. Under this condition, the LDLR is not available for a lower affinity binding with Lp(a) as it is mainly engaged in the removal of LDL. Other receptors possibly involved in Lp(a) uptake might be controlled by PCSK9. The increased levels of PCSK9 may lead to an increased formation of PCSK9–Lp(a) (and/or LDL) complexes. (C) In the presence of anti-PCSK9 mAb, extracellular PCSK9 is sequestered; thus, LDLR is recycled to the surface and available for new binding. The reduction of PCSK9 reduces the production of Lp(a) particles through several mechanisms. Lp(a)–PCSK9 complexes may be recognized by the anti-PCSK9 mAb, promoting an alternative removal pathway. (D) In the presence of statin and mAb to PCSK9, both LDLR expression and recycling are increased, leading to a massive reduction of LDL particles. This increases the number of free LDLRs, which are thus available for low affinity binding with Lp(a), leading to an increased Lp(a) uptake. Other receptors may contribute to removal of Lp(a). An alternative explanation may be based on the fact that experimental and clinical evidence suggests the involvement of additional receptors/pathways in the clearance of Lp(a).15 Although evolocumab reduced LDL-C levels only marginally in two HoFH patients carrying complete loss-of-function LDLR mutations, it significantly reduced their Lp(a) levels despite the absence of any LDLR,16 indicating the possible involvement of other pathways, perhaps also intracellular. Some additional receptors have been suggested as likely to be involved in Lp(a) clearance; among them, the two members of the LDLR family VLDLR and megalin/LRP2,15 plasminogen receptors, scavenger receptor type B class I (SR-BI), and sortilin have also been proposed.15,17 The role of these receptors in the catabolism of Lp(a) is still largely unexplored, as is the possible involvement of PCSK9 in regulating their expression. An alternative explanation that deserves consideration is that as PCSK9 also binds to Lp(a),18 one could speculate that, in statin-treated patients, the increased amount of circulating PCSK9 leads to a higher percentage of Lp(a)–PCSK9 complexes, which in turn are recognized by the antibodies, promoting an alternative antibody-driven removal pathway Finally a word of caution on the methodology; although the careful nature of the work is appreciated, issues about the methodology and data analysis are still present. Isolating apo(a) and Lp(a)–apoB specifically-derived peptides is not an easy task, and the studies of isotopic enrichment clearly depend on these processes. Further, the theoretical modelling with the different compartments also heavily depends on these data, and small changes may preferentially favour one pathway over another. In summary, to date, the mechanisms by which PCSK9 inhibition reduces Lp(a) levels are unclear, and the conflicting results reported in the studies of Watts11 and Reyes-Soffer12 confirm the complexity of Lp(a) metabolism and the fact that biology in not as simple as we tend to believe; several regulatory pathways can be in place, and dissecting their relative role is quite challenging. Clearly we need future studies addressing those aspects to understand, by the use of appropriate in vitro and ex vivo approaches, the complexity of adaptive responses to pharmacological interventions that nature offers to us. Conflict of interest: A.L.C reports grants from Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, and Eli Lilly; and personal fees from Astrazeneca, Genzyme, Bayer, SigmaTau, Menarini, Kowa, Eli Lilly, Recordati, Pfizer, Sanofi, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, and Amgen, outside the submitted work. A.P. has no conflicts to declare. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. †doi:10.1093/eurheartj/ehy122. References 1 Nordestgaard BG , Chapman MJ , Ray K , Boren J , Andreotti F , Watts GF , Ginsberg H , Amarenco P , Catapano A , Descamps OS , Fisher E , Kovanen PT , Kuivenhoven JA , Lesnik P , Masana L , Reiner Z , Taskinen MR , Tokgozoglu L , Tybjaerg-Hansen A. Lipoprotein(a) as a cardiovascular risk factor: current status . Eur Heart J 2010 ; 31 : 2844 – 2853 . Google Scholar CrossRef Search ADS PubMed 2 Yeang C , Wilkinson MJ , Tsimikas S. Lipoprotein(a) and oxidized phospholipids in calcific aortic valve stenosis . Curr Opin Cardiol 2016 ; 31 : 440 – 450 . Google Scholar CrossRef Search ADS PubMed 3 Boffa MB , Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 2016 ; 57 : 745 – 757 . Google Scholar CrossRef Search ADS PubMed 4 Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies . J Am Coll Cardiol 2017 ; 69 : 692 – 711 . Google Scholar CrossRef Search ADS PubMed 5 van Capelleveen JC , van der Valk FM , Stroes ES. Current therapies for lowering lipoprotein(a) . J Lipid Res 2016 ; 57 : 1612 – 1618 . Google Scholar CrossRef Search ADS PubMed 6 Vogt A. Lipoprotein(a)-apheresis in the light of new drug developments . Atheroscler Suppl 2017 ; 30 : 38 – 43 . Google Scholar CrossRef Search ADS PubMed 7 Raal FJ , Giugliano RP , Sabatine MS , Koren MJ , Blom D , Seidah NG , Honarpour N , Lira A , Xue A , Chiruvolu P , Jackson S , Di M , Peach M , Somaratne R , Wasserman SM , Scott R , Stein EA. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role . J Lipid Res 2016 ; 57 : 1086 – 1096 . Google Scholar CrossRef Search ADS PubMed 8 Gaudet D , Watts GF , Robinson JG , Minini P , Sasiela WJ , Edelberg J , Louie MJ , Raal FJ. Effect of alirocumab on lipoprotein(a) over ≥1.5 years (from the Phase 3 ODYSSEY Program) . Am J Cardiol 2017 ; 119 : 40 – 46 . Google Scholar CrossRef Search ADS PubMed 9 Lamon-Fava S. Statins and lipid metabolism: an update . Curr Opin Lipidol 2013 ; 24 : 221 – 226 . Google Scholar CrossRef Search ADS PubMed 10 Couture P , Lamarche B. Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond . Curr Opin Lipidol 2013 ; 24 : 227 – 232 . Google Scholar CrossRef Search ADS PubMed 11 Watts GF , Chan DC , Somaratne R , Wasserman SM , Scott R , Marcovina SM , Barrett PHR. Controlled study of the effect of proprotein convertase subtilisin–kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics . Eur Heart J 2018 ; 39 : 2577 – 2585 . 12 Reyes-Soffer G , Pavlyha M , Ngai C , Thomas T , Holleran S , Ramakrishnan R , Karmally W , Nandakumar R , Fontanez N , Obunike J , Marcovina SM , Lichtenstein AH , Matthan NR , Matta J , Maroccia M , Becue F , Poitiers F , Swanson B , Cowan L , Sasiela WJ , Surks HK , Ginsberg HN. Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans . Circulation 2017 ; 135 : 352 – 362 . Google Scholar CrossRef Search ADS PubMed 13 Chan D , Barret PH , Marcovina SM , Coll Crespo B , Somaratne R , Rob S , Wasserman SM , Watts GF. Apolipoprotein(a) isoform size may influence the production and catabolism of lipoprotein(a) particles in men . Atherosclerosis 2017 ; 263 : e26 . 14 Villard EF , Thedrez A , Blankenstein J , Croyal M , Tran TT , Poirier B , Le Bail JC , Illiano S , Nobecourt E , Krempf M , Blom DJ , Marais AD , Janiak P , Muslin AJ , Guillot E , Lambert G. PCSK9 modulates the secretion but not the cellular uptake of lipoprotein(a) ex vivo: an effect blunted by alirocumab . JACC Basic Transl Sci 2016 ; 1 : 419 – 427 . Google Scholar CrossRef Search ADS PubMed 15 Hoover-Plow J , Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets . Metabolism 2013 ; 62 : 479 – 491 . Google Scholar CrossRef Search ADS PubMed 16 Stein EA , Honarpour N , Wasserman SM , Xu F , Scott R , Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia . Circulation 2013 ; 128 : 2113 – 2120 . Google Scholar CrossRef Search ADS PubMed 17 Yang XP , Amar MJ , Vaisman B , Bocharov AV , Vishnyakova TG , Freeman LA , Kurlander RJ , Patterson AP , Becker LC , Remaley AT. Scavenger receptor-BI is a receptor for lipoprotein(a) . J Lipid Res 2013 ; 54 : 2450 – 2457 . Google Scholar CrossRef Search ADS PubMed 18 Tavori H , Christian D , Minnier J , Plubell D , Shapiro MD , Yeang C , Giunzioni I , Croyal M , Duell PB , Lambert G , Tsimikas S , Fazio S. PCSK9 association with lipoprotein(a) . Circ Res 2016 ; 119 : 29 – 35 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: Jun 2, 2018
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