Metabolic effects of PCSK9 inhibition with Evolocumab in subjects with elevated Lp(a)

Xiang Zhang, Lotte C A Stiekema, Erik S G Stroes, Albert K Groen, Xiang Zhang, Lotte C A Stiekema, Erik S G Stroes, Albert K Groen

Abstract

Background: Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized.

Methods: We performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo (N = 14) and evolocumab (N = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses.

Results: On average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P < 0.001) reduction of circulating Lp(a), coupled with substantial reduction of VLDL, IDL and LDL particles as well as their lipid contents. Interestingly, increasing concentrations of baseline Lp(a) were associated with larger reduction in triglyceride-rich VLDL particles after evolocumab treatment.

Conclusions: Inhibition of PCSK9 with evolocumab markedly reduced VLDL particle concentrations in addition to lowering LDL-C. The extent of reduction in VLDL particles depended on the baseline level of Lp(a). Our findings suggest a marked effect of evolocumab on VLDL metabolism in subjects with elevated Lp(a).

Trial registration: Clinical trial registration information is registered at ClinicalTrials.gov on April 14, 2016 with the registration number NCT02729025.

Keywords: Evolocumab; Lipoprotein(a); Metabolomics; PCSK9 antibodies; VLDL.

Conflict of interest statement

E.S.G.S. reports that his institution has received lecturing fees and advisory board fees from Amgen Inc., Regeneron, Sanofi, Akcea, Novartis and Athera. All other authors declared no conflict of interest.

Figures

Fig. 1
Fig. 1
Mean difference in lipoprotein particle concentrations between evolocumab and palacebo group, adjusting for pre-treatment lipoprotein particle concentrations. Circles represent the posterior mean difference. Lines refer to the 95% credible intervals
Fig. 2
Fig. 2
Reduction of medium VLDL particles correlated with baseline lipoprotein(a) concentrations. Every circle represents the posterior mean reduction of medium VLDL particle concentration and the posterior mean of baseline lipoprotein(a) in a patient treated with evolocumab. The vertical and horizontal bar represents the 95% credible interval. The blue dashed line represented the average percentage (50%) change in medium VLDL particle after evolocumab treatment

References

    1. Cain WJ, Millar JS, Himebauch AS, Tietge UJF, Maugeais C, Usher D, et al. Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. Journal of lipid research [internet]. 2005;46:2681–91. Available from: .
    1. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation [internet]. 2019;139:1483–92. Available from: .
    1. Van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein (a). Journal of lipid research [internet]. 2016;57:1612–8. Available from: , .
    1. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, et al. 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. Journal of the American College of Cardiology [internet]. 2014;63:1278–88. Available from: .
    1. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Seidah NG, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. Journal of lipid research [internet]. 2016;57:1086–96. Available from: , .
    1. Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. The journal of biological chemistry [internet]. 2015;290:11649–62. Available from: , .
    1. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. European heart journal [internet]. 2019;1:1–10. Available from: .
    1. Reyes-Soffer G, Pavlyha M, Ngai C, Thomas T, Holleran S, Ramakrishnan R, et al. Effects of PCSK9 inhibition with Alirocumab on lipoprotein metabolism in healthy humans. Circulation [internet]. 2017;135:352–62. Available from: , .
    1. Watts GF, Chan DC, Somaratne R, Wasserman SM, Scott R, Marcovina SM, et al. Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics. European heart journal [internet]. 2018;39:2577–85. Available from: .
    1. Stoekenbroek RM, Lambert G, Cariou B, Hovingh GK. Inhibiting PCSK9 - biology beyond LDL control. Nature reviews endocrinology [internet]. Springer US; 2018;15:52–62. Available from: 10.1038/s41574-018-0110-5,.
    1. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, et al. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. The journal of biological chemistry [internet]. 2008;283:2363–72. Available from: .
    1. Demers A, Samami S, Lauzier B, Des Rosiers C, Ngo Sock ET, Ong H, et al. PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arteriosclerosis, thrombosis, and vascular biology [internet]. 2015;35:2517–25. Available from: .
    1. Argraves KM, Kozarsky KF, Fallon JT, Harpel PC, Strickland DK. The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. The journal of clinical investigation [internet]. 1997;100:2170–81. Available from: , .
    1. Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell metabolism [internet]. Elsevier Inc 2010;12:467–82. Available from: 10.1016/j.cmet.2010.09.010, , .
    1. Dijk W, Le May C, Cariou B. Beyond LDL: What role for PCSK9 in triglyceride-rich lipoprotein metabolism? Trends in endocrinology and metabolism: TEM [internet]. Elsevier Ltd; 2018;29:420–34. Available from: 10.1016/j.tem.2018.03.013, .
    1. Kettunen J, Demirkan A, Würtz P, Draisma HHM, Haller T, Rawal R, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nature communications [internet]. 2016;7:11122. Available from: , .
    1. Sliz E, Kettunen J, Holmes M, Williams C, Boachie C, Wang Q, et al. Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment. Circulation [internet]. 2018;138:2499–512. Available from: , .
    1. Stiekema LCA, Stroes ESG, Verweij SL, Kassahun H, Chen L, Wasserman SM, et al. Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. European heart journal [internet]. 2018;31:1–8. Available from: .
    1. Soininen P, Kangas AJ, Würtz P, Tukiainen T, Tynkkynen T, Laatikainen R, et al. High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism. The analyst [internet]. 2009;134:1781–5. Available from: .
    1. Würtz P, Wang Q, Soininen P, Kangas AJ, Fatemifar G, Tynkkynen T, et al. Metabolomic profiling of statin use and genetic inhibition of HMG-CoA Reductase. Journal of the American College of Cardiology [internet]. 2016;67:1200–10. Available from: , .
    1. Toth PP, Sattar N, Blom DJ, Martin SS, Jones SR, Monsalvo ML, et al. Effect of Evolocumab on lipoprotein particles. The American journal of cardiology [internet]. Elsevier Inc. 2018;121:308–14. Available from: 10.1016/j.amjcard.2017.10.028, .
    1. Yang X-P, Amar MJ, Vaisman B, Bocharov AV, Vishnyakova TG, Freeman LA, et al. Scavenger receptor-BI is a receptor for lipoprotein(a). Journal of lipid research [internet]. 2013;54:2450–7. Available from: , .
    1. Sharma M, Redpath GM, Williams MJA, McCormick SPA. Recycling of Apolipoprotein(a) after PlgRKT-mediated endocytosis of lipoprotein(a). Circulation research [internet]. 2017;120:1091–102. Available from: .
    1. McConathy WJ, Trieu VN, Koren E, Wang CS, Corder CC. Triglyceride-rich lipoprotein interactions with Lp(a). Chemistry and physics of lipids [internet]. 1994;67-68:105–13. Available from: .
    1. Gaubatz JW, Hoogeveen RC, Hoffman AS, Ghazzaly KG, Pownall HJ, Guevara J, et al. Isolation, quantitation, and characterization of a stable complex formed by Lp[a] binding to triglyceride-rich lipoproteins. Journal of lipid research [internet]. 2001;42:2058–68. Available from: .

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