<p>Inclisiran for the Treatment of Cardiovascular Disease: A Short Review on the Emerging Data and Therapeutic Potential</p>

Abstract

Proprotein convertase subtilisin kexin 9 (PCSK-9)-targeting therapy has arisen as a new line for the treatment of hyperlipidemia. Inclisiran is a double-stranded small RNA molecule that works by blocking the transcription of PCSK-9, leading to a reduction of PCSK9 levels in the hepatocytes, resulting in an increased expression of low-density lipoprotein (LDL) receptors in the hepatocyte membrane and, as a consequence, it reduces the circulating levels of LDL cholesterol (LDL-C). Compared to the other LDL-C-lowering medications, such as statins, ezetimibe and PCSK-9 inhibitors, inclisiran proposes an infrequent dosing of twice a year, while simultaneously providing a significant reduction of LDL-C. Its prolonged effect offers an advantage against medication non-compliance, which is one of the main causes for not achieving LDL-C goals with standard therapy. Inclisiran has also proven to have a relatively safe profile with adverse effects occurring in similar frequency as with placebo. This review aims to present and discuss the current clinical and scientific data pertaining to the role of inclisiran in the management of hypercholesterolemia and treatment of cardiovascular disease (CVD).

Antiplatelet Effects of PCSK9 Inhibitors in Primary Hypercholesterolemia

“…Inclisiran is a relatively new drug that was authorized for use by the European Medicines Agency in December 2020. It is a silencing RNA (siRNA) particle targeting the hepatic production of PCSK9 [ 86 ]. Inclisiran selectively interferes with the expression of specific genes and catalytically silences the translation of the complementary target messenger RNA (mRNA), blocking the synthesis of PCSK9 [ 86 ].…”

“…It is a silencing RNA (siRNA) particle targeting the hepatic production of PCSK9 [ 86 ]. Inclisiran selectively interferes with the expression of specific genes and catalytically silences the translation of the complementary target messenger RNA (mRNA), blocking the synthesis of PCSK9 [ 86 ]. Clinical trial data showed a 44% reduction in LDL-C level compared to placebo in heterozygous FH, and a 50% reduction in general hypercholesterolemic patients [ 87 , 88 ].…”

“…Clinical trial data showed a 44% reduction in LDL-C level compared to placebo in heterozygous FH, and a 50% reduction in general hypercholesterolemic patients [ 87 , 88 ]. In contrary to mAbs, inclisiran needs to be administered twice a year, which is more convenient for patients than the twice-a-month injection of mAbs [ 86 ].…”

Presente y futuro del tratamiento hipolipemiante, nuevas moléculas a la vista

“…The reported mechanism of action is reduction of intra and extracellular production of PCSK9, from conjugation with triantennary N-acetylgalactosamine (GalNAc) that provides high-affinity binding to hepatocyte receptors, which reduce the dose and volume of drug required and the highly specific liver uptake should result in less chance of off-target effects. 13,14 Efficacy on LDL-C reduction has been demonstrated in phase II and III ORION studies, with participation of more than twenty thousand patients worldwide, 14 who were under maximum dosing of statins and/or more ezetimibe and with significant risk factors for cardiovascular disease, achieving a reduction in LDL-C of approximately 50%, allowing up to six months between doses.…”

<p>Safety and Tolerability of PCSK9 Inhibitors: Current Insights</p>

“…On the other hand, other potential therapeutic strategies targeting PCSK9 are in development, including inclisiran (a small interfering RNA [siRNA] molecule), other small molecule inhibitors that disrupt the processing of PCSK9, as well as adnectins, which block the binding of PCSK9 to the LDLR. [71][72][73]…”