Preventing premature cardiovascular death
Dawn of a new era in lowering low density lipoprotein cholesterol
Reducing low density lipoprotein (LDL) cholesterol is the priority in managing patients with severe dyslipidaemia (cholesterol abnormality) and at high risk of cardiovascular (CV) death and disability. Yet even when treated with potent statins, many patients fail to achieve LDL-cholesterol targets and therefore their risk of accelerated atherosclerosis and CV death remains high.
This problem is particularly critical in patients with familial hypercholesterolaemia (FH) (the most commonly occurring genetic condition in the world). People with FH typically have very high LDL cholesterol levels on treatment, and consequently, are at very high risk of premature and sudden CV death, myocardial infarction and stroke. Additionally, some patients are unable to tolerate statins – particularly at higher doses – and, therefore, do not achieve LDL-cholesterol goals.
What is the importance of PCSK9?
Discovered in 2003,1 PCSK9 is a protein made by the liver which increases the removal of LDL receptors from the surface of liver cells. These LDL receptors are critically important in removal of serum LDL-cholesterol from the circulation.
People with so-called ‘gain of function’ PCSK9 mutations over-express PCSK9, and therefore have very high plasma levels of LDL cholesterol and are at very risk of atherosclerosis and CV mortality and morbidity.2
In contrast, people with so-called ‘loss of function’ PCSK9 mutations, have very LDL cholesterol levels and reduced risk for heart disease.3
What is PCSK9 inhibition?
A number of fully human monoclonal antibodies that inhibit PCSK9 are in clinical development.
Trials show that these PCSK9 inhibitors reduce LDL cholesterol levels by about 50-60 percent - a significantly greater effect than that achieved with currently available therapies – either when given alone or in combination. These LDL cholesterol lowering effects have been consistently across a broad group of patients, including those with familial hypercholesterolaemia in clinical trials.4
What is the potential clinical role of PCSK9 inhibitors?
Researchers and clinicians suggest that PCSK9 inhibition with these monoclonal antibodies may reduce CV risk in patients whose clinical needs cannot be satisfied by current therapy. These include:
- Patients with familial hypercholesterolaemia – an inherited disorder of lipid metabolism with a very high risk of early CV death or morbidity, if not diagnosed or treated early
- Patients who cannot tolerate statins, who therefore remain at high risk of CV events such as heart attacks and strokes
- Patients with established heart disease who have not achieved LDL-cholesterol goals despite current therapies
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|⇧1, ⇧2||Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6. http://www.ncbi.nlm.nih.gov/pubmed/12730697|
|⇧3||Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72. http://www.ncbi.nlm.nih.gov/pubmed/16554528|
|⇧4||Stein EA, Raal F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9. Annu Rev Med 2014;65:417-31. http://www.ncbi.nlm.nih.gov/pubmed/24422577|