pcsk9 education and research forum
Alcester
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? Different
approaches to lowering PCSK9 are now licensed. These include fully human
monoclonal antibodies (alirocumab, evolocumab) and a small-interfering RNA
therapy (inclisiran). 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 Which clinical settings will benefit
from the availability of PCSK9 inhibitors? These treatments offer the potential
to reduce cardiovascular 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
