Treatments

General picture

Over the last ten years there has not been much progress. Pharmaceutical researchers have tried to use other methods. It has been noted that three clinical trials were undertaken to look at HDL, but either failed or stopped.

Statins

A category of medicines, called statins, are the primary drugs to lower LDL. Statins are usually well tolerated and considered very safe. A few people have difficulty in taking statins – according to information on the HEART UK website, research has shown that 10-15% of patients treated with a statin show some degree of intolerance, with many people stopping their statin within a year of its prescription.
Statins are not, however, suitable for women who are trying to conceive, who are pregnant or breastfeeding (as with all the drugs as there is no safety data available. The possible exception is bile acids which do not get absorbed). Statins are not routinely prescribed for young children, but are licensed for use in children under care of a paediatric specialist.

For a very small number of patients with high cholesterol, statins are not effective. According to research, in patients with familial hypercholesterolaemia (FH), high intensity statins can reduce LDL cholesterol by only 50% at maximum and in general monotherapy with statins is not usually sufficient to get a FH patient to goal.

The HEART UK website offers a helpful list of questions on statins treatments: – https://heartuk.org.uk/statins-and-treatments/statin-side-effects/the-statin-conundrum

Ezetimibe

This is another medicine used to lower LDL cholesterol. It is a medication that blocks the absorption of cholesterol from food and bile juices in your intestines into your blood. Ezetimibe monotherapy is recommended as an option for treating primary (heterozygous-familial or non-familial) hypercholesterolaemia in adults who cannot tolerate statin therapy. Ezetimibe taken on its own rarely causes side effects. In certain cases ezetimibe is co-administered with initial statin therapy when serum total or low-density lipoprotein (LDL) cholesterol concentration is not appropriately controlled. The side effects of the combined statin and ezetimibe treatment are generally the same as those of the statin on its own (muscle pain and stomach problems).

Bile acid sequestrants

These medicines are used to lower LDL cholesterol

Lomitapide

This type of medication can be used to treat homozygous familial hypercholesterolaemia. It is termed a ‘microsomal triglyceride transfer protein (MTP) inhibitor’. In other words, it limits the amount of cholesterol that your liver makes, so that your body has less cholesterol to remove from the blood stream. The commercial name for lomitapide is Juxtapid in the US and Lojuxta in the EU. At present this medication is very expensive and requires strict adherence to a low fat diet as it may cause fat build-up in liver, leading to fatty liver.

Mipomersen

Mipomersen sodium is a cholesterol-lowering drug for use as an adjunct to diet and drug therapy in patients with homozygous hypercholesterolaemia. Clinical studies with the drug found that it raised liver enzymes and led to an accumulation of fat in the liver. This drug is available in the United States, but in 2012 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended refusal of marketing authorisation, based on side effects of this drug.

Lipoprotein apheresis

Lipoprotein apheresis is a medical therapy which may be used for patients who are not able to meet their LDL cholesterol goal with medicines and lifestyle changes. Apo B-containing lipoproteins (LDL, vLDL and Lp(a)) are physically removed from the blood. Following a filtration process, the newly filtered blood, with a much lower LDL level, is returned. Medical professionals monitor patients during the procedure, which takes two to three hours. The treatment is generally performed every second week. Lipoprotein apheresis is most commonly used to treat patients with FH, but is also often used for other hyperlipidaemia patients, including those with elevated Lp(a), to limit and/or reverse the atherosclerotic complications of high cholesterol.

Latest developments:

PCSK9i

The development of this treatment reflects the role of medical genetics, the branch of medicine which involves the diagnosis and management of hereditary disorders. The PCSK9 (full name “proproptein convertase substilisin/kexin type 9) gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream. The PCSK9 protein appears to control the number of low-density lipoprotein (LDL) receptors, which are proteins on the surface of cells. The LDL receptor (LDLR) is found on the surface of the liver and plays a critical role in regulating LDL cholesterol levels in the circulation. The receptors bind to particles called (LDLs) which are the primary carriers of cholesterol in the blood and they help remove them. The fewer receptors there are, the less able the liver is to keep blood cholesterol low.

Studies have shown that some people have a great deal of PCSK9 protein and that when it is more abundant and active, it leads to life-long high cholesterol and early heart disease.

A new class of medications called PCSK9 inhibitors (referred to as PCSK9i) target the PCSK9 protein making it less effective at breaking down the LDL receptors. This means that there are then more working receptors on the surface of liver cells and more cholesterol can be removed from the blood. The PCSK9 inhibitors that have now been developed are called ‘monoclonal antibodies’ and they are produced in medical laboratories under strict controls. Each monoclonal antibody can recognise just one particular protein. The monoclonal antibodies recognise and attach to specific proteins produced by the cells in one’s body. The abbreviation for monoclonal antibody is ‘mab’ and so PCSK9i drugs all end in the three letters ‘mab’. Evolocumab and Alirocumab are licensed in the United Kingdom for example, but are not yet available in all European countries.

This type of drug cannot be taken orally – PCSK9 Inhibitors are given as injections under the skin every 2 to 4 weeks.

Volanesorsen’ using ‘antisense technology’

In August 2017, American pharmaceutical company ‘Akcea Therapeutics’ an affiliate of Ionis Pharmaceuticals, Inc., submitted a New Drug Application to the American Federal Drug Association (FDA) for a drug it has developed called ‘volanesorsen’. Various clinical trials have taken place with the aim of developing treatment of Familial Chylomicronaemia Syndrome (FCS) and Familial Partial Lipodystrophy (FPL).

FCS is an inherited metabolic disorder that causes a build-up of triglycerides (fats) in the blood: this can increase the risk of severe abdominal pain and potentially fatal attacks of pancreatitis. Due to a deficiency in lipoprotein lipase, an enzyme that helps to break down triglycerides, people who have FCS are unable to effectively metabolise large, triglyceride-rich lipid particles called chylomicrons. This genetic condition is also sometimes known as lipoprotein lipase deficiency (LPLD), Fredrickson Type 1 hyperlipoproteinemia and familial hypertriglyceridemia.

Familial partial lipodystrophy (FPL) is a severe, rare genetic metabolic disorder which results in high levels of triglycerides in the bloodstream, abnormal fat distribution around and within organs, such as the liver and heart and a range of metabolic anbnormalities, including severe insulin resistance. In addition to an increased risk of pancreatitis, other long-term, progressive manifestations such as premature cardiomyopathy, atherosclerosis and liver disease may occur.

Volanesorsen uses Ionis’ ‘antisense technology’, a technique described by academic researchers a decade ago as “a potentially powerful therapeutic tool for gene targeting and/or expression regulation”. Volanesorson is designed to reduce the production of ApoC-III, a protein produced in the liver that plays a central role in the regulation of plasma triglycerides and may also affect other metabolic parameters.