Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab

Michael D Shapiro, Jessica Minnier, Hagai Tavori, Helina Kassahun, Andrea Flower, Ransi Somaratne, Sergio Fazio, Michael D Shapiro, Jessica Minnier, Hagai Tavori, Helina Kassahun, Andrea Flower, Ransi Somaratne, Sergio Fazio

Abstract

Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.

Trial registration: ClinicalTrials.gov NCT01763827 NCT01763866 NCT01763905 NCT01763918.

Keywords: lipid‐lowering therapy; lipoprotein[a]; low‐density lipoprotein cholesterol; proprotein convertase subtilisin/kexin type 9.

Figures

Figure 1
Figure 1
Relationship between percentage reduction in LDL‐C and Lp(a). Relationship between percentage reduction in LDL‐C and Lp(a) at 12 weeks of evolocumab therapy according to baseline Lp(a). A, Baseline Lp(a) >10 mg/dL. B, Baseline Lp(a) >30 mg/dL, C, Baseline Lp(a) >50 mg/dL. The quadrants shaded in pink represent patients with discordant LDL‐C and Lp(a) responses to evolocumab based on response to therapy defined as LDL‐C reduction >35% and Lp(a) reduction >10%. LDL‐C indicates low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); Q2W, every 2 weeks; QM, monthly.
Figure 2
Figure 2
Relationship between percentage reduction in Lp(a) and selected variables. Relationship between percentage reduction in Lp(a) and baseline LDL‐C (A), on‐treatment LDL‐C (B), and baseline Lp(a) concentration (C) for the overall cohort at 12 weeks of evolocumab therapy. LDL‐C indicates low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a).

References

    1. Maxwell KN, Breslow JL. Adenoviral‐mediated expression of Pcsk9 in mice results in a low‐density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA. 2004;101:7100–7105.
    1. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators . Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722.
    1. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; Committees OO, Investigators . Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107.
    1. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, Kim JB, Scott R, Wasserman SM, Bays H; MENDEL‐2 Investigators . Anti‐PCSK9 monotherapy for hypercholesterolemia: the MENDEL‐2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–2540.
    1. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, Sullivan D, Hovingh GK, Cariou B, Gouni‐Berthold I, Somaratne R, Bridges I, Scott R, Wasserman SM, Gaudet D; RUTHERFORD‐2 Investigators . PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD‐2): a randomised, double‐blind, placebo‐controlled trial. Lancet. 2015;385:331–340.
    1. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, Bruckert E, Cho L, Dent R, Knusel B, Xue A, Scott R, Wasserman SM, Rocco M; GAUSS‐2 Investigators . Anti‐PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS‐2 randomized, placebo‐controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541–2548.
    1. Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014;114:711–715.
    1. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278–1288.
    1. 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.
    1. Albers JJ, Kennedy H, Marcovina SM. Evidence that Lp[a] contains one molecule of apo[a] and one molecule of apoB: evaluation of amino acid analysis data. J Lipid Res. 1996;37:192–196.
    1. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium . Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–2528.
    1. Dati F, Tate JR, Marcovina SM, Steinmetz A; International Federation of Clinical Chemistry and Laboratory Medicine, IFCC Working Group for Lipoprotein(a) Assay Standardization . First WHO/IFCC international reference reagent for lipoprotein(a) for immunoassay—Lp(a) SRM 2B. Clin Chem Lab Med. 2004;42:670–676.
    1. Edmiston JB, Brooks N, Tavori H, Minnier J, Duell B, Purnell JQ, Kaufman T, Wojcik C, Voros S, Fazio S, Shapiro MD. Discordant response of low‐density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9. J Clin Lipidol. 2017;11:667–673.
    1. 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.
    1. Kamstrup PR, Tybjaerg‐Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–2339.
    1. Myers GL, Cooper GR, Winn CL, Smith SJ. The Centers for Disease Control‐National Heart, Lung And Blood Institute Lipid Standardization Program. An approach to accurate and precise lipid measurements. Clin Lab Med. 1989;9:105–135.
    1. Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, Somaratne R, Legg JC, Nelson P, Scott R, Wasserman SM, Weiss R; LAPLACE‐2 Investigators . Effect of evolocumab or ezetimibe added to moderate‐ or high‐intensity statin therapy on LDL‐C lowering in patients with hypercholesterolemia: the LAPLACE‐2 randomized clinical trial. JAMA. 2014;311:1870–1882.
    1. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69:692–711.
    1. Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol. 2016;36:2239–2245.
    1. Yeang C, Witztum JL, Tsimikas S. ‘LDL‐C’ = LDL‐C + Lp(a)‐C: implications of achieved ultra‐low LDL‐C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL‐C lowering. Curr Opin Lipidol. 2015;26:169–178.
    1. Welcome to AmgenTrials. Available at: . Accessed: December 24, 2018.
    1. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta‐analysis of prospective studies. Circulation. 2000;102:1082–1085.
    1. Lamon‐Fava S, Marcovina SM, Albers JJ, Kennedy H, Deluca C, White CC, Cupples LA, McNamara JR, Seman LJ, Bongard V, Schaefer EJ. Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study. J Lipid Res. 2011;52:1181–1187.
    1. Li Y, Luke MM, Shiffman D, Devlin JJ. Genetic variants in the apolipoprotein(a) gene and coronary heart disease. Circ Cardiovasc Genet. 2011;4:565–573.
    1. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38:1553–1560.
    1. Eaton DL, Fless GM, Kohr WJ, McLean JW, Xu QT, Miller CG, Lawn RM, Scanu AM. Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. Proc Natl Acad Sci USA. 1987;84:3224–3228.
    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; European Atherosclerosis Society Consensus Panel . Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–2853.
    1. Hoover‐Plow J, Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism. 2013;62:479–491.
    1. 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.
    1. Kostner KM, Kostner GM. Lipoprotein (a): a historical appraisal. J Lipid Res. 2017;58:1–14.
    1. 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.
    1. Moriarty PM, Varvel SA, Gordts PL, McConnell JP, Tsimikas S. Lipoprotein(a) mass levels increase significantly according to APOE genotype: an analysis of 431 239 patients. Arterioscler Thromb Vasc Biol. 2017;37:580–588.
    1. Berg K. A new serum type system in man—the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382.
    1. Tsimikas S, Fazio S, Viney NJ, Xia S, Witztum JL, Marcovina SM. Relationship of lipoprotein(a) molar concentrations and mass according to lipoprotein(a) thresholds and apolipoprotein(a) isoform size. J Clin Lipidol. 2018;12:1313–1323.

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