Universität zu Köln

Katzmann, Julius L., Gouni-Berthold, Ioanna and Laufs, Ulrich (2020). PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects. Front. Physiol., 11. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-042X

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Abstract

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2-4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of similar to 46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Katzmann, Julius L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gouni-Berthold, Ioanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Laufs, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-311328
DOI:	10.3389/fphys.2020.595819
Journal or Publication Title:	Front. Physiol.
Volume:	11
Date:	2020
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-042X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; HIGH CARDIOVASCULAR RISK; SUBTILISIN/KEXIN TYPE 9; CHRONIC KIDNEY-DISEASE; LDL-CHOLESTEROL; STATIN THERAPY; DOUBLE-BLIND; SECONDARY ANALYSIS; COST-EFFECTIVENESS; RANDOMIZED-TRIAL Multiple languages Physiology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31132