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Antisense lipoprotein[a] therapy: State-of-the-art and future perspectives

Published:April 24, 2020DOI:https://doi.org/10.1016/j.ejim.2020.04.036

      Highlights

      • Lp[a] is a significant risk factor for many cardiovascular disorders.
      • Most medical treatments for lowering high Lp[a] concentration have technical and clinical drawbacks.
      • Antisense therapy targeting either apo[a] or apoB is currently being developed.
      • Anti-apoB antisense therapy is effective to lower LDL between 18–33% and LDL between 26–39%.%
      • Anti-apo[a] antisense therapy is effective to lower Lp[a] between 35–80% and LDL between 6–16%.%

      Abstract

      Several lines of evidence now attest that lipoprotein[a] (Lp[a]) is a significant risk factor for many cardiovascular disorders. This enigmatic lipoprotein, composed of a single copy of apolipoprotein B (apoB) and apolipoprotein[a] (apo [a]), expresses peculiar metabolism, virtually independent from lifestyle interventions. Several therapeutic options have hence been proposed for lowering elevated Lp[a] values, with or without concomitant effect on low density lipoprotein (LDL) particles, mostly encompassing statins, ezetimibe, nicotinic acid, lipoprotein apheresis, and anti-PCSK9 monoclonal antibodies. Since all these medical treatments have some technical and clinical drawbacks, a novel strategy is currently being proposed, based on the use of antisense apo[a] and/or apoB inhibitors. Although the role of these agents in hypercholesterolemic patients is now nearby entering clinical practice, the collection of information on Lp[a] is still underway. Preliminary evidence would suggest that apo[a] antisense therapy seems more appropriate in patients with isolated Lp[a] elevations, while apoB antisense therapy is perhaps more advisable in patients with isolated LDL elevations. In patients with concomitant elevations of Lp[a] and LDL, either combining the two apo[a] and apoB antisense therapies (a strategy which has never been tested), or the combination of well-known and relatively inexpensive drugs such as statins with antisense apo[a] inhibitors can be theoretically suggested. The results of an upcoming phase 3 study with antisense apo[a] inhibitors will hopefully provide definitive clues as to whether this approach may become the standard of care in patients with increased Lp[a] concentrations.

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