Inclisiran for the treatment of hypercholesterolaemia

Abstract

Inclisiran is a synthetic small interfering RNA (siRNA) that inhibits the production of proprotein convertase subtilisin/kexin 9 (PCSK9) in hepatocytes by silencing the translation of PCSK9 mRNA. The result of this mechanism is a decrease in PCSK9 synthesis resulting in decreased degradation of the LDL receptor, leading to more LDL receptors being available to clear LDL cholesterol (LDL-C) from the circulation. Inclisiran received FDA approval in 2021 and EMA approval in 2020. The indication for inclisiran use is as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidaemia, including those with heterozygous familial hypercholesterolaemia to reduce LDL-C. Inclisiran has demonstrated consistent LDL-C lowering in the range of 44-54%. Furthermore, inclisiran has been demonstrated to be a safe medication with indications of significant or serious adverse events when compared to placebo. Inclisiran is given as an initial subcutaneous dose followed by a repeat dose at 3 months and every 6 months thereafter. The 2022 American College of Cardiology Expert Consensus Decision Pathway includes inclisiran as an option for non-statin therapy in addition to maximally tolerated statin therapy in those at very high risk of atherosclerotic cardiovascular disease or those with LDL-C >190 mg/dL. The ORION-4, VICTORION-1 PREVENT and VICTORION-2 PREVENT trials are ongoing and designed to evaluate the ability of inclisiran to reduce major cardiovascular events in addition to LDL-C lowering but will not be completed for a few years.

Keywords: atherosclerotic cardiovascular disease; cardiovascular events; dyslipidaemia; heterozygous familial hypercholesterolaemia; hypercholesterolaemia; hyperlipidaemia; inclisiran; proprotein convertase subtilisin/kexin 9; small interfering RNA.