PCSK9-Inhibitoren – Durchbruch bei der LDL-Cholesterin-Senkung?

Zusammenfassung

Die Proproteinkonvertase-Subtilisin / Kexin-Typ-9 (PCSK9) spielt eine wichtige Rolle im LDL-Cholesterin(LDL-C)-Stoffwechsel. So weisen Menschen mit Mutationen im PCSK9-Gen, die zu einer Funktionseinschränkung des Enzyms führen, deutlich erniedrigte LDL-C-Plasmaspiegel auf. PCSK9 wird in der Leber sezerniert, bindet an den LDL-Rezeptor und bewirkt, dass er mit dem gebundenen LDL-C lysosomal abgebaut wird. Bei den derzeitigen PCSK9 Inhibitoren handelt es sich um monoklonale Antikörper, die PCSK9 spezifisch binden und funktionell neutralisieren. Somit kann der Rezeptor vom LDL-C dissoziieren und wird nicht abgebaut, sondern recycelt, was die LDL Rezeptordichte der Hepatozyten erhöht und die LDL-C Clearance steigert. Die subkutan applizierten PCSK9 Inhibitoren Alirocumab und Evolocumab bewirkten in klinischen Studien Senkungen des LDL-C von maximal ca. 70 % bei mit Statin behandelten und unbehandelten Patienten. Das Nebenwirkungspotenzial erscheint bisher vertretbar. Weil diese Wirkstoffe einen hohen klinischen Nutzen erwarten lassen, wurden sie von der EMA im Sommer 2015 bereits vor Abschluss der Studien zu patientenrelevanten Endpunkten (kardiovaskuläre Morbidität und Mortalität) zugelassen. Eine bessere Beurteilung des tatsächlichen Nutzens sowie der Langzeitsicherheit der PCSK9-Inhibitoren wird erst nach Publikation der Ergebnisse der Outcome-Studien ab 2017 möglich sein.

Abstract

The proprotein convertase subtilisin / kexin type 9 (PCSK9) plays an important role in LDL cholesterol (LDL-C) metabolism. Subjects harboring loss-of-function mutations in the gene encoding for PCSK9 display markedly reduced LDL-C plasma levels. PCSK9 is secreted by the liver, binds to the LDL receptor and, following endocytosis, induces lysosomal degradation of the receptor together with the bound LDL-C. Current PCSK9 inhibitors are monoclonal antibodies that specifically absorb PCSK9. Subsequently, instead of being degraded the receptor can dissociate from LDL-C and recycle, consecutively resulting in an increased hepatocyte LDL receptor density and higher LDL-C clearance. In clinical trials, the PCSK9 inhibitors alirocumab and evolocumab induced reductions in LDL-C of up to 70 % in statin-treated as well as statin-naïve patients. So far, serious side effects (requiring cessation of drug treatment) occurred only in rare cases. Since this new class of lipid lowering drugs promises a high potential benefit, they have been approved by the EMA even before completion of the studies addressing clinically relevant endpoints like cardiovascular events and mortality. Therefore, the expected publication of these study results in 2017 may allow a better assessment of the efficacy and safety of PCSK9 inhibitors.

Schlüsselwörter

PCSK9-Inhibitoren - Evolocumab - Alirocumab - LDL-Cholesterin - kardiovaskuläre Erkrankungen

Keywords

PCSK9 inhibitors - evolocumab - alirocumab - LDL cholesterol - cardiovascular disease

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