Inclisiran

Inclisiran is recommended as a treatment option in treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults.

Familial hypercholesterolaemia is characterised by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. (1)

Lowering LDL-C levels is therefore a key part of all cardiovascular disease prevention guidelines, which recommend matching the intensity of LDL-C lowering with the absolute risk of the patient. Unfortunately, issues such as statin intolerance or difficulties with long-term adherence to statin therapy and a subsequent inability to achieve desired LDL-C levels with statins alone results in a continuing raised cardiovascular disease risk. (2)

Pharmacologic management of familial hypercholesterolaemia includes the use of high-intensity statins, ezetimibe, and monoclonal antibodies directed against circulating PCSK9.

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

Note - there have been concerns raised concerning the NICE technology appraisal for inclisiran (see related page) (5)

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. 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 (6).

Reference:

1. Amor-Salamanca A, Castillo S, Gonzalez-Vioque E, et al. Genetically confirmed familial hypercholesterolemia in patients with acute coronary syndrome. J Am Coll Cardiol 2017;70:1732-1740.
2. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
3. Warden BA, Duell PB. Inclisiran: a novel agent for lowering apolipoprotein B–containing lipoproteins. J Cardiovasc Pharmacol. 2021;78:e157–e174.
4. NICE. Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia. Technology appraisal guidance TA733. Published October 2021
5. Byrne P et al. NICE guidance on inclisiran should be reconsidered. BMJ 2021; 375
6. 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.)