Inclisiran

Inclisiran is a new treatment for people with high cholesterol, or high cholesterol and triglycerides, that’s not being reduced enough with other treatments. It’s given by injection every three to six months.

Inclisiran (brand name Leqvio) can be used to lower high cholesterol whether or not it’s caused by a genetic condition. It can also be used to treat mixed dyslipidaemia, where you have raised levels of both cholesterol and triglycerides.

Inclisiran is specifically for people whose cholesterol is not adequately controlled with first line medications such as statins, ezetimibe, or ezetimibe with bempedoic acid (in those who are statin intolerant). It can be prescribed by GPs and other health professionals in primary and secondary care.

How does inclisiran work?

Inclisiran works in a similar way to another treatment called PCSK9 inhibitors (Evolocumab and Alirocumab) because it blocks the action of a protein called PCSK9. This protein is released by liver cells and raises cholesterol.  

What is the PCSK9 protein?

Liver cells have LDL receptors on their surface. These capture LDL cholesterol ('bad cholesterol') as it passes by in the blood, pulling it into the liver to be broken down. Once the LDL receptor is emptied of cholesterol, it returns to the liver cell surface where it can be used again, or ‘recycled’.

The PCSK9 protein prevents the recycling of LDL receptors. They are destroyed instead. This means there are fewer LDL receptors and this slows the removal of LDL cholesterol from the blood (keeping blood levels high).    

Why are statins sometimes not enough?

When you take cholesterol-lowering treatments such as statins and ezetimibe, the liver makes more PCSK9 protein, which reduces the effect of the treatment (because there are fewer LDL receptors to take cholesterol out of the blood).

Treatments that block the PCSK9 protein and stop it destroying LDL receptors (including inclisiran) therefore help make sure you have enough LDL receptors available to remove the LDL cholesterol,  lowering the LDL cholesterol in your blood. 

How do other PCSK9 inhibitors help?

The current PCSK9 inhibitors (Evolocumab and Alirocumab) are a type of medication known as monoclonal antibodies. These bind tightly to the PCSK9 protein and block it from working so that there are more LDL receptors on the liver cells and less cholesterol in the blood.

They are currently only prescribed in a secondary care or hospital setting for people who meet strict prescription criteria , as required by NICE (the National Institute for Health and Care Excellence, who set guidelines for health professionals). They are usually given every two to four weeks by injection.

 

How can inclisiran help?

Inclisiran is known as an siRNA, also known as small interfering RNA (RNA interference). It works differently from the PCKS9 inhibitors by interrupting the “printing” of PCSK9 protein from the genetic template known as messenger RNA. 

By stopping the PCSK9 protein being made in the liver, more LDL receptors can return to the surface of the liver and continue to remove LDL cholesterol from the blood.  This interruption of PCSK9 printing lasts much longer than the other PCSK9 inhibitors and other cholesterol-lowering drugs, meaning inclisiran only needs to be given every three to six months.

Who can have inclisiran? 

Inclisiran can be used in combination with a statin and other treatments to lower blood fats. 

 

In Scotland and Wales

Inclisiran has the same prescription criteria as PCSK9 inhibitors. It can be used for:

  • those with familial hypercholesterolaemia, if your LDL cholesterol is above 5mmol/L
  • those with known cardiovascular disease (including heart disease) at specific LDL cholesterol levels depending on the extent of your disease.

Find out more from the Scottish Medicines Consortium (SMC) and the All Wales Therapeutics and Toxicology Centre (AWTTC).

In England

NICE has approved different prescription criteria in England. Inclisiran is only available for those who already have known cardiovascular disease, as a 'secondary prevention' treatment to prevent further problems such as heart attacks or strokes. This includes those who have or have had:

  • a heart attack
  • unstable angina needing hospitalisation
  • coronary or other arterial revascularization such as an angioplasty or coronary artery bypass
  • a stroke
  • peripheral vascular disease

plus

  • an LDL cholesterol level of 2.6mmol/l or more, despite the maximum dose of other treatments to lower blood fats (such as statins with or without other medicines, or other treatments when statins cannot be taken).

Find out more at NICE Technology Appraisal 733.

Inclisiran Q&A

How do you take inclisiran?
Inclisiran is given by injection under the skin, usually in the abdomen, upper arm or thigh. It will be given by a health professional. 

How often do you need injections?
Inclisiran is a long-term treatment. After the first dose, the next dose will be given after three months, then you will only need it every six months.

What dose will you need?
The recommended dose of inclisiran is 284mg for each injection. There are no adjustments needed. 

How much does it lower cholesterol?
Clinical trial evidence shows that inclisiran can lower LDL cholesterol levels by at least 50%. 

How quickly does it work?
Near-maximum reductions in LDL cholesterol levels are seen from 90 days of treatment.  

How much does it cost?
Inclisiran is available on the NHS.

Does inclisran lower the risk of cardiovascular disease?
There is currently no long-term evidence to show whether inclisiran can help prevent events such as heart attacks and strokes.  

Is there any ongoing research?
Orion 4 is an ongoing randomised controlled trial (a high quality type of study) using inclisiran vs placebo (a dummy drug) in people with a history of cardiovascular disease. This is due to finish in 2026.

There are plans for a randomised controlled trial to study the effectiveness of inclisiran vs placebo in those who do not have existing cardiovascular disease (this is known as a primary prevention trial). This trial is called Orion 17.

The main outcomes for both trials are cardiovascular events such as heart attacks and stroke, and death.

Can you take inclisiran with a PCSK9 inhibitor? 
PCSK9 inhibitors and inclisiran should not be given together because they both target the PCSK9 protein, and there would be no extra benefit to taking both.

Are there any side effects?
Like all medications, some people may experience side effects, but inclisiran is generally very safe and well tolerated. The most common side effects reported include pain and redness or rash at the injection site. It does not interact with other medications.

Will you need any monitoring?
Your doctor or other health professional will let you know if you need any further blood tests. Your cholesterol can be checked three months after the first injection, before the second dose.