Author's reply

Abstract

I appreciate the interest and comments from Dr Bandyopadhyay and colleagues about my recently published review article regarding PCSK9 inhibition in the Journal of Cardiology [[1]Ogura M. PCSK9 inhibition in the management of familial hypercholesterolemia.J Cardiol. 2017; PubMed Google Scholar]. I agree with them that inclisiran is a hopeful and promising drug to manage hyperlipidemic patients including those with familial hypercholesterolemia (FH). As they stated, inclisiran is a long-acting double-stranded small RNA interference therapeutic molecule targeting PCSK9 mRNA, and the pharmacodynamic profile of inclisiran differs from that of the anti-PCSK9 antibodies. The effect of inclisiran on the PCSK9 and low-density lipoprotein (LDL) cholesterol levels persisted for at least 180 days after the initiation of treatment in the Phase 1 trial [[2]Fitzgerald K. White S. Borodovsky A. Bettencourt B.R. Strahs A. Clausen V. et al.A highly durable RNAi therapeutic inhibitor of PCSK9.N Engl J Med. 2017; 376: 41-51Crossref PubMed Scopus (232) Google Scholar] and the Phase 2 trial [[3]Ray K.K. Landmesser U. Leiter L.A. Kallend D. Dufour R. Karakas M. et al.Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol.N Engl J Med. 2017; 376: 1430-1440Crossref PubMed Scopus (573) Google Scholar]. Indeed, statins require daily administration and adherence is an important issue. However, in the management of FH, statins should be a first-line drug and treatment with PCSK9 inhibitor alone would be insufficient. As I stated in this review article, the effect of statin in increasing LDL receptor expression (LDL-cholesterol reducing effect) would be limited in FH patients with LDL receptor mutations or those that have PCSK9 gain of function mutations that promote LDL receptor degradation. Since statins upregulate both LDL receptor and PCSK9 via SREBP2, co-administration of statin and PCSK9 inhibitor is a good strategy to manage heterozygous FH patients. If safety and cost of inclisiran are the same or better than anti-PCSK9 monoclonal antibody, inclisiran may be an alternative to alirocumab or evolocumab. It is also interesting that anti-PCSK9 monoclonal antibodies act on the extracellular level (intravascular level) while inclisiran acts on the intracellular level of hepatocytes to decrease the level of LDL-cholesterol and PCSK9. Inclisiran is a fully chemically modified, small interfering RNA conjugated to the triantennary N-acetylgalactosamine (GalNAc). This conjugate is specifically recognized by the asialoglycoprotein receptor (ASGPR) that is highly expressed on the surface of liver hepatocytes [[4]Khvorova A. Oligonucleotide therapeutics – a new class of cholesterol-lowering drugs.N Engl J Med. 2017; 376: 4-7Crossref PubMed Scopus (93) Google Scholar], therefore, inclisiran might be said to be appropriate for liver-specific therapy while anti-PCSK9 antibodies are for systemic therapy. As I mentioned in this review article, PCSK9 is reportedly expressed in the small intestine and is involved in lipid absorption. In systemic knockout mice of PCSK9, it was found that serum triglyceride levels did not increase after fat loading. Interestingly, it was reported that evolocumab has a modest effect on cholesterol synthesis and absorption despite significant LDL-cholesterol lowering in a human study [[5]Peach M. Xu R. Fitzpatrick D. Hamilton L. Somaratne R. Scott R. et al.Effect of evolocumab on cholesterol synthesis and absorption.J Lipid Res. 2016; 57: 2217-2224Crossref PubMed Scopus (12) Google Scholar]. Accordingly, it seems that there are no differences in cholesterol absorption between inclisiran and evolocumab. However, I think that differences in postprandial plasma triglyceride levels and chylomicron production between these drugs should be investigated. Additionally, PCSK9 is also expressed in vascular smooth muscle cells in atherosclerotic plaque and is involved in enhancing inflammation in atherosclerotic plaque and decreased cholesterol efflux from macrophages. It means both systemic (from hepatocytes) and local (from vascular smooth muscle cells) PCSK9 may affect atherosclerotic plaque progression. Although the GLAGOV study demonstrated significant plaque regression efficacy for evolocumab, the anti-inflammatory effect of this drug was not discussed. Therefore, it remains to be elucidated whether anti-PCSK9 antibodies have more anti-inflammatory property than inclisiran. In summary, I also look forward to using inclisiran. Understanding the differences between anti-PCSK9 monoclonal antibodies and inclisiran may shed new light on biology as well as pathophysiology of PCSK9. I will keep my eyes on the safety, cost, and extra-hepatic actions of PCSK9 inhibitors and pay attention to the future trends of PCSK9 inhibition in the management of FH.