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Review
. 2023 Sep 9:54:1-6.
doi: 10.1016/j.athplu.2023.09.001. eCollection 2023 Dec.

Lipoprotein(a), Interleukin-6 inhibitors, and atherosclerotic cardiovascular disease: Is there an association?

Anastasios Makris  1 , Fotios Barkas  2   3 , Petros P Sfikakis  4 , Evangelos Liberopoulos  4 , Theodosios D Filippatos  5 , Kausik K Ray  3 , Aris P Agouridis  6   7
Affiliations
Review

Lipoprotein(a), Interleukin-6 inhibitors, and atherosclerotic cardiovascular disease: Is there an association?

Anastasios Makris et al. Atheroscler Plus. .

Abstract

Background and aims: Lipoprotein(a) [Lp(a)] and interleuking-6 (IL-6), an inflammation biomarker, have been established as distinct targets of the residual atherosclerotic cardiovascular disease (ASCVD) risk. We aimed to investigate the association between them, and the potential clinical implications in ASCVD prevention.

Methods: A literature search was conducted in PubMed until December 31st, 2022, using relevant keywords.

Results: Elevated lipoprotein(a) [Lp(a)] levels constitute the most common inherited lipid disorder associated with ASCVD. Although Lp(a) levels are mostly determined genetically by the LPA gene locus, they may be altered by acute conditions of stress and chronic inflammatory diseases. Considering its resemblance with low-density lipoproteins, Lp(a) is involved in atherosclerosis, but it also exerts oxidative, thrombotic, antifibrinolytic and inflammatory properties. The cardiovascular efficacy of therapies lowering Lp(a) by >90% is currently investigated. On the other hand, interleukin (IL)-1b/IL-6 pathway also plays a pivotal role in atherosclerosis and residual ASCVD risk. IL-6 receptor inhibitors [IL-6(R)i] lower Lp(a) by 16-41%, whereas ongoing trials are investigating their potential anti-atherosclerotic effect. The Lp(a)-lowering effect of IL-6(R)i might be attributed to the inhibition of the IL-6 response elements in the promoter region of the LPA gene.

Conclusions: Although the effect of IL-6(R)i on Lp(a) levels is inferior to that of available Lp(a)-lowering therapies, the dual effect of the former on both inflammation and apolipoprotein (a) synthesis may prove of equal or even greater significance when it comes ASCVD outcomes. More trials are required to establish IL-6(R)i in ASCVD prevention and elucidate their interplay with Lp(a) as well as its clinical significance.

Keywords: Atherosclerotic cardiovascular disease; IL-6; IL-6 inhibitor; Interleukin 6; Lipoprotein(a); Lp(a).

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fotios Barkas has received honoraria from Amgen, Novartis, Novo Nordisc and Viatris.Petros P Sfikakis has received consultant fees from Actelion, Pfizer, Genesis, MSD, UCB, Boehringer Ingelheim, Enorasis, Farmaserv-Lilly, Gilead, Abbvie, and Novartis. He has received grants and research support from Abbvie, Roche, Pfizer, Faran, Amgen, Jannsen, Boehringer Ingelheim, and Gilead.Evangelos Liberopoulos reports personal fees and non-financial support from Amgen, personal fees from Servier, personal fees from Boehringer-Ingelheim, personal fees and non-financial support from AstraZeneca, personal fees from MSD, personal fees from Lilly, personal fees and non-financial support from Bayer, personal fees from Novartis, personal fees from Chiesi, outside the submitted work.Theodosios D. Filippatos reports participation in advisory board for Lilly and lecture honoraria from Boehringer Ingelheim, Mylan, Astra Zeneca, Lilly, Recordati, Bausch Health, Servier, Viatris, Omega-Pharma and Innovis.Kausik K. Ray has received honoraria for consulting, lectures from Kowa, Amgen, Regeneron Pharmaceuticals, Sanofi, Daiichi Sankyo, Pfizer, Viatris, AstraZeneca, Eli Lilly, Esperion, New Amsterdam Pharma, Novartis, Silence Therapeutics, Bayer, Boehringer Ingelheim, Novo Nordisk, SCRIBE, CRISPR, Cargene, Vaxxinity, Abbott, Resverlogix. In addition, he has received research grant support to his institution from Sanofi, Daiichi Sankyo, Amgen, Pfizer and MSD and support from the NIHR Imperial Biomedical Research Centre.Anastasios Makris and Aris P. Agouridis have no conflict of interest to declare.

Figures

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Graphical abstract
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