Hypercholestrolaemia Flashcards
What is hypercholesterolaemia and causes
when total plasma cholesterol is > 6.5mmol/l. ideal level is <5.2mmol/l.
25-30% of middle aged pop have hypercholesterolaemia. particularly important is if it is high LDL-C or low HDL-C.
a major risk factor in atherosclerosis.
Atherosclerosis caused by damage to blood vessel walls that leads to inflammation - macrophage and monocyte infiltration. this leads to deposition of foam cells in the blood vessels and subsequent formation of cholesterol rich atherosclerotic plaques. Growth of this leads to stenosis - narrowing of blood vessel lumen, causing symptoms of ischaemia in angina. rupturing of the plaque can lead to clot formation and occlusion of the artery.
smoking, dyslipidaemia, diabetes, hypertension and ageing are risk factors.
Statins mechanism
they are HMG-CoA reductase inhibitors, preventing the formation of mevalonate which is an intermediate in the formation of cholesterol.
They decrease cholesterol synthesis in hepatocytes and increase LDL receptor expression. This increases the uptake of LDL-C.
the LDL-R binds to LDL-C and internalises it, where LDL-C is then removed and the LDL-R is returned to the plasma membrane
PCSK9 function
it is a serine protease.
mice over expressed with PCSK9 have decreased LDL-R and higher LDL-C levels. conversely knockout led to increased LDL-R and reduced LDL-C.
PCSK9 binds to the LDL-R internalising it and subsequently degrading it in lysosomes.
Statins are found to increase PCSK9 activity which reduces their effectiveness.
PCSK9 targeting drugs
PCSK9 inhibitors lead to reduced breakdown of LDL-R and thus more LDL-C is taken up into hepatocytes.
Alirocumab and evolocumab are mAbs for PCSK9. given as monthly injections
ACD0780 is a phase 1 small molecule oral inhibitor of PCSK9
inclisiran is an siRNA that inhibits IC synthesis of PCSK9. It binds to an RNA-induced silencing complex (RISC) and the siRNA is unwound into a single strand that binds to complementary mRNA. The RISC then degrades the bound mRNA. a risk of longer siRNA is that they can lead to immune reactions and global silencing of genes - cell death.
in order for the siRNA to enter in the cytoplasm they need a carrier: nano carriers, aptamers, antibodies, proteins, peptides or sugar/amino sugars.
Lipoprotein targeting drug
olpasiran , a siRNA that interferes with the production of apolipoprotein(a), a component of LDL.
used to treat atherosclerosis.
Cholesterol ester transfer protein (CETP) inhibitors
obicetrapib is in clinical trials.
it targets CETP, a plasma glycoprotein produced in liver and adipose. it circulates in the blood bound to HDL. it is involved in the transfer of cholesterol esters from HDL to either VLDL or LDL, therefore inhibiting CETP leads to increased levels of HDL-C.
when used at higher doses leading to greater inhibition, it also leads to a lowering of LDL-C levels
torcetrapib which also targets CETP was found to increase mortality in clinical trials. it increased BP slightly, with only small increase in [HDL-C].
dalcetrapib, evacetrapib and anacetrapib trials were abandoned due to lack of efficacy
Combining anacetrapib with a. statin was found to reduce cardiovascular risks. obicetrapib with a statin is currently in clinical trials, and there is potential for CETP + PCSK9i combination therapy.
