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PCSK9-Hemmung – ein Update

Update on PCSK9 inhibition

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Zusammenfassung

Die therapeutische Senkung des LDL(„low-density lipoprotein“)-Cholesterins ist einer der effektivsten Maßnahmen in der kardiovaskulären Prävention. Neben der oralen Therapie mit Statinen, Ezetimib und Bempedoinsäure haben sich subkutan applizierte Inhibitoren der Proproteinkonvertase Subtilisin/Kexin Typ 9 (PCSK9) als weitere Säule der lipidsenkenden Therapie etabliert. Die alle 2 bis 4 Wochen subkutan zu verabreichenden Antikörper Evolocumab und Alirocumab senken das LDL-Cholesterin unabhängig von der Vorbehandlung um rund 60 % bei sehr guter Verträglichkeit. Für beide Wirkstoffe liegen positive Endpunktstudien vor. Ein neues Prinzip zur PCSK9-Inhibition ist die RNA-Interferenz, welche mit dem Wirkstoff Inclisiran genutzt wird. Bei Inclisiran handelt es sich um ein doppelsträngiges modifiziertes RNA-Molekül, welches die mRNA von PCSK9 neutralisiert und damit die PCSK9-Proteinsynthese intrazellulär hemmt. Inclisiran muss nur halbjährlich appliziert werden. Die Endpunktstudie ORION‑4 läuft gegenwärtig. Die Verschreibung von PCSK9-Hemmern ist in Deutschland durch einen Beschluss des Gemeinsamen Bundesausschusses reglementiert. Neue Strategien zur PCSK9-Hemmung sind in Entwicklung und umfassen u. a. oral verfügbare Wirkstoffe und tierexperimentelle Konzepte zur Gentherapie, welche sich in unterschiedlichen Stadien der Prüfung befinden.

Abstract

Lowering of low-density lipoprotein (LDL) cholesterol represents one of the most effective interventions in cardiovascular prevention. Besides the oral treatment with statins, ezetimibe and bempedoic acid, subcutaneously administered inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) have been established as further cornerstones of lipid-lowering treatment. The antibodies evolocumab and alirocumab are administered subcutaneously every 2–4 weeks and lower LDL cholesterol by around 60%, independent of pre-treatment with very good tolerability. Both drugs successfully reduced cardiovascular endpoints in large outcome trials. A novel principle of PCSK9 inhibition is RNA interference, which is exploited by the novel compound inclisiran. Inclisiran is a double-stranded modified RNA molecule, which neutralizes the mRNA of PCSK9 and thus inhibits PCSK9 protein synthesis intracellularly. Inclisiran only needs to be administered every 6 months. The cardiovascular outcome trial ORION‑4 is currently ongoing. In Germany, prescription of PCSK9 inhibitors is regulated by the decision of the Federal Joint Committee. Novel strategies to inhibit PCSK9 function are under development and include orally available drugs and animal experiment concepts on gene editing, which are in different states of evaluation.

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Danksagung

Die Autoren danken Isabell Katzmann für die Erstellung der Abbildungen 1 und 3.

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Authors and Affiliations

  1. Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstraße 20, 04103, Leipzig, Deutschland

    Julius L. Katzmann & Ulrich Laufs

  2. Klinik für Innere Medizin II, Klinikum Saarbrücken, Saarbrücken, Deutschland

    Florian Custodis

  3. Kardiopraxis Schirmer, Kaiserslautern, Deutschland

    Stephan H. Schirmer

  4. Klinik für Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Deutschland

    Stephan H. Schirmer

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  1. Julius L. Katzmann
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  4. Ulrich Laufs
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Correspondence to Julius L. Katzmann.

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Interessenkonflikt

J.L. Katzmann gibt an, dass kein Interessenkonflikt besteht. F. Custodis, S.H. Schirmer und U. Laufs haben Honorare für Vorträge von Amgen, Daiichi Sankyo, Novartis und Sanofi erhalten.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Katzmann, J.L., Custodis, F., Schirmer, S.H. et al. PCSK9-Hemmung – ein Update. Herz 47, 196–203 (2022). https://doi.org/10.1007/s00059-022-05112-y

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