What is cholesterol and how does Inclisiran work to lower it?

Cholesterol is a waxy substance found in your blood. Cholesterol comes from two sources; all of the cholesterol your body needs to function is produced by your liver, with any additional cholesterol coming from animal-based food products, such as meat, poultry and dairy products. Cholesterol is carried through your blood attached to proteins, forming lipoproteins. There are different types of cholesterol in your blood, depending on what type the lipoprotein carries. The main two types are:

• Low-density lipoprotein – the ‘bad’ cholesterol, which transports cholesterol particles throughout the body. If there is too much circulating in the bloodstream, LDL cholesterol can build up in the walls of arteries, making them harder and narrower.
• High-density lipoprotein – the ‘good’ cholesterol, which picks up excess cholesterol and takes it back to the liver.

Cholesterol plays a vital role in your body’s normal functioning, and there is cholesterol in every one of your cells. It is especially important in your brain, nerves and skin. A vital component of cell membranes, it is also important in hormones and vitamin production, and is used to make bile, which helps to digest fats in your gut. However, although your body needs cholesterol to build healthy cells, high levels of cholesterol in your blood can increase the risk of heart disease.

High cholesterol can cause a dangerous accumulation of cholesterol deposits in arterial walls, forming plaques, known as atherosclerosis. These deposits can reduce blood flow through your arteries and can lead to complications, ranging from chest pain (angina) through to heart attacks and strokes.

Despite the gloomy complications that can result, lowering your blood cholesterol levels, particularly LDL cholesterol levels, is one of the most effective ways of reducing your risk of developing cardiovascular disease.

There are several ways you can do this, simply by changing a few lifestyle choices:

• Cutting down on fatty foods, particularly those high in saturated fats such as red meat, butter, cream and hard cheeses, cakes and biscuits and foods containing coconut or palm oil.
• Instead, try to eat more oily fish such as mackerel and salmon, brown rice, bread and pasta, nuts and seeds, and plenty of fruits and vegetables.
• In addition, try to do at least 150 minutes (2.5 hours) of exercise every week, particularly cardiovascular exercises such as walking, swimming and cycling.
• Try to quit smoking if you do, and if you drink, try to avoid drinking more than 14 units of alcohol a week.

A healthy lifestyle is the first defence against high cholesterol. But sometimes diet and exercise aren’t enough. In these cases, you may need to take cholesterol medications to help lower your blood cholesterol levels. Your doctor might suggest a single drug or a combination of cholesterol medications. The most commonly available are:

• Statins. (eg atorvastatin, simvastatin, rosuvatatin). These decrease LDL and triglyceride levels in the blood.
• Ezetimibe. A cholesterol absorption inhibitor. This is generally taken in conjunction with a statin.
• PCSK-9 inhibitors. Usually reserved for people who have a genetic condition that causes very high LDL levels, or people with heart disease who cannot tolerate statins or other cholesterol-lowering drugs. Given as an injection every 2 weeks.(eg Repatha- evolocumab or Praluent-alirocumab)
• Nilmedo -Bempedoic acid. A citrate lyase (an enzyme involved in cholesterol production) inhibitor. Usually given in conjunction with statins, particularly where statins have failed to sufficiently lower LDL levels.

Most cholesterol medications lower blood cholesterol with few side effects, however, their effectiveness varies from person-to-person. Furthermore, even if you are prescribed cholesterol-lowering medications, it is still important to follow a healthy diet and get regular exercise, in order to have the best chance of reducing your risk of heart attacks and stroke.

Inclisiran is the first of a new class of cholesterol-lowering treatments using RNA interference (RNAi) to boost the liver’s ability to remove harmful cholesterol (low-density lipoproteins (LDLs)) from the blood.

RNA has got into the news recently in light of some of the COVID-19 vaccines using mRNA technology, notably the Pfizer and Moderna vaccines. RNA (ribonucleic acid) is used during protein production inside our cells.

Inclisiran is a small interfering RNA that inhibits translation of the protein PCSK9, which binds to the receptor for LDL particles. The LDL receptor (LDLR) on liver cell membranes, binds and initiates ingestion of LDL-particles into cells, thus reducing LDL particle concentrations in the blood. If PCSK9 is blocked, more LDLRs are recycled and are present on the cell surfaces to remove LDL-particles. Therefore, blocking PCSK9 binding can lower blood LDL-particle concentrations.

This novel anti-cholesterol drug, the first of its kind approved anywhere in the world, might be given in primary care as a twice-yearly injection if other drugs have failed to sufficiently reduce blood cholesterol levels. With two doses a year and effective and sustained LDL cholesterol reduction, Inclisiran works as a complement to statins. Inclisiran works differently from other therapies by preventing the production of the target protein in the liver, increasing hepatic uptake of LDL-cholesterol and clearing it from the bloodstream. Administered in the doctors surgery as a subcutaneous injection, Inclisiran may become widely used in the NHS.

1. Book a cardiology assessment, where your risk of cardiovascular complications will be assessed.
2. Not everyone needs statins, and even if they were recommended, they are not a substitute for healthy lifestyle factors, such as quitting smoking, losing excess weight, controlling your blood pressure and getting regular exercise in reducing your cholesterol levels.
3. After your cardiovascular assessment, you should ask your cardiologist what options there are available to you.
4. If drugs are recommended, try statins as your first line – they have the largest evidence base in reducing blood cholesterol and with respect to long-term outcomes.
5. If more expensive drugs are needed, then we can assess you for them.