Inclisiran

Inclisiran is indicated for the treatment of primary hypercholesterolaemia or mixed dyslipidaemia [in combination with a statin, or with a statin and other lipid-lowering therapies, or with other lipid-lowering therapies or alone if a statin contra-indicated or not tolerated].

PCSK9 is a circulating protein primarily produced and secreted by hepatocytes that regulates LDL receptor half-life in the liver. It functions primarily by altering LDL receptor recycling via binding the receptor and facilitating its transport into lysosomes for degradation (3)

Inclisiran (Leqvio 248mg) is a small interfering RNA that inhibits PCSK9, thereby upregulating the number of LDL-receptors on the hepatocytes. It is administered by subcutaneous injection twice a year, after an initial baseline and 3 month dose.

It is recommended only if (4):

• there is a history of any of the following cardiovascular events:
  • acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)
  • coronary or other arterial revascularisation procedures
  • coronary heart disease
  • ischaemic stroke or
  • peripheral arterial disease, and
• low-density lipoprotein cholesterol (LDL-C) concentrations are persistently 2.6 mmol/l or more, despite maximum tolerated lipid-lowering therapy, that is
  • maximum tolerated statins with or without other lipid-lowering therapies or,
  • other lipid-lowering therapies when statins are not tolerated or are contraindicated

Evidence of cardiovascular benefit of inclisiran

• results are also being awaited from the ORION-4 trial: a double-blind randomised placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease (3):
  • this study aims to find out whether inclisiran, given every 6 months for about 5 years, safely reduces the risk of heart attacks, strokes or the need for urgent coronary angioplasty or bypass grafts, in people who already have known vascular disease
• in a patient-level analysis of phase III trials (4)
  • with respect to a prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke
    • inclisiran significantly reduced composite MACE, but not fatal and non-fatal MIs or fatal and non-fatal stroke
  • the study authors concluded that:
    • this analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction
    • these findings await confirmation in the larger CV outcomes trials of longer duration (ORION-4)

Reference:

1. Warden BA, Duell PB. Inclisiran: a novel agent for lowering apolipoprotein B–containing lipoproteins. J Cardiovasc Pharmacol. 2021;78:e157–e174.
2. NICE. Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia. Technology appraisal guidance TA733. Published October 2021
3. NHS Health Research Authority. ORION-4. HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease. 2025. (Online.)
4. Ray KK, Raal FJ, Kallend DG, Jaros MJ, Koenig W, Leiter LA, Landmesser U, Schwartz GG, Lawrence D, Friedman A, Garcia Conde L, Wright RS; ORION Phase III investigators. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2023 Jan 7;44(2):129-138.