NICE guidance - Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia

NICE states (1):

Inclisiran is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. It is recommended only if:

• 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, and
• the company provides inclisiran according to the commercial arrangement

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 (2):
  • 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 (3)
  • 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. NICE. Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia. Technology appraisal guidance TA733. Published October 2021
2. 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.)
3. 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.