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

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. A literature search was conducted in PubMed until December 31st, 2022, using relevant keywords. 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. 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. IL-6 axis and its association with lipoprotein(a) and atherosclerotic cardiovascular diseaseDamage-associated molecular patterns (DAMPs) trigger the assembly and activation of the NOD-like receptor family pyrin domain containing 3 (NLPR3) inflammasome, which, via caspase-1-mediated cleavage of pro-interleukin-1β (proIL-1b), leads to IL-1b production. IL-1b induces its own production, as well as that of IL-6. In turn, IL-6 acts on the liver and induces the production of acute phase reactants, including plasminogen activator inhibitor-1 (PAI-1) and fibrinogen, both of which have thrombogenic properties. In addition, IL-6 induces apolipoprotein(a) [apo(a)] synthesis by triggering the promoter region of the LPA ge