4.2 Hyperlipidaemia

Question 1

how do we obtain cholesterol?

Answer 1

Most cholesterol synthesised in body with contribution (~25%) from diet

Question 2

what is the function of cholesterol?

Answer 2

Essential for membrane integrity, precursor in production of steroid hormones, bile acids and
vitamin D (vitamin C requires cholesterol in epidermis to form vitamin D from sunlight)

Question 3

why is LDL known as bad cholesterol?

Answer 3

LDL have very long life span and are susceptible to oxidation at damaged endothelium, ROS contributes to endothelial dysfunction increasing adherence of lipid rich deposits and foam cells formed – precursor to
atheromatous plaques

Question 4

why is HDL known as good cholesterol?

Answer 4

HDL carrier of cholesterol away from circulation to tissues that require it and the liver for disposal in bile

Question 5

what is the units of cholesterol?

Answer 5

mmol/L

Question 6

why is cholesterol a target in reducing CVD risk?

Answer 6

As it is a modifiable risk factor

data shows relationship between elevated cholesterol and morbidity and mortality from CHD

Question 7

what are risk factors for suffering from a significant cardiovascular event?

Answer 7

left ventricular hypertrophy
diabetes
high cholesterol
hypertension
male

Question 8

give some examples of statins

Answer 8

atorvastatin 
simvastatin
fluvastatin 
pravastatin 
rosuvastatin 
lovastatin

Question 9

what is the mechanism of action of statins?

Answer 9

Competitive inhibition of HMG-CoA reductase – rate controlling enzyme in HMG-
CoA to mevalonate pathway
Low intracellular cholesterol contributes to upregulation of hepatic LDL receptors, increasing the clearance of circulating LDL
low intracellular cholesterol also decreases the secretion of VLDL

Question 10

what other benefits do statins have aswell as lowering cholesterol?

Answer 10

• Improved vascular endothelial function - ↑NO, vascular endothelial growth factor, ↓endothelin
• Stabilisation of atherosclerotic plaque - ↓smooth muscle cell proliferation ↑collagen
• Improved haemostasis - ↓plasma fibrinogen, platelet aggregation, ↑fibrinolysis
• Anti-inflammatory - ↓proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines
• Antioxidant - ↓superoxide formation

Question 11

what is the major difference in the pharmacokinetics of simvastatin and atorvastatin?

Answer 11

the half life of simvastatin is 2 hours, and the half life for atorvastatin is 24 hours

Question 12

what are the adverse drug reactions of statins?

Answer 12

GI disruption, nausea and headache
myalgia – diffuse muscle pain (↑Creatine phosphokinase >5 X normal limit) - dose related)
Rarely – rhabdomyolysis
Increased liver enzymes

Question 13

what are the contraindications of statins?

Answer 13

renal or hepatic impairment

pregnancy! and breastfeeding

Question 14

what are the drug interactions of statins?

Answer 14

CYP 3A4 important – amiodarone, diltiazem, macrolides - increases [plasma] statin
Remember amlodipine (CCB) also increases [plasma] statin

Question 15

what is the first line statin?

Answer 15

atorvastatin

Question 16

what are the common indications of atorvastatin?

Answer 16

used to reduce LDL cholesterol levels
• Primary prevention 20 mg atorvastatin once daily (10 year CVD risk of >10% using QRISK)
• Secondary prevention 80 mg atorvastatin once daily

Question 17

why is grapefruit juice not advised for patients on statins?

Answer 17

as grapefruit juice inhibits CYP 3A4, a cytochrome responsible for the metabolism of statins

Question 18

why is it advised that simvastatin is taken at night?

Answer 18

as has relatively short half life and LDL receptor synthesis has a circadian rhythm that primarily happens at night

Question 19

what is a nocebo effect?

Answer 19

The idea that some patients perceive that they are going to have a side effect and so report that they do have it. this is detrimental as if patient believes that the drug is having side effects then the adherence of the treatment goes down.

Question 20

give an example of a fibric acid derivate?

Answer 20

fenofibrate

Question 21

what is the mechanism of action of fenofibrate?

Answer 21

Activation of nuclear transcription factor – PPARα
(peroxisome proliferation-activated receptor)
PPARα regulate expression of genes that control lipoprotein metabolism - increase production of lipoprotein lipase .This results in:
↑triglycerides from lipoprotein in plasma
↑fatty acid uptake by the liver ↑levels of HDL
↑LDL affinity for receptor •

Question 22

what are the indications for fibric acid derivatives?

Answer 22

co-prescribed in familial hyperlipidaemia

Question 23

what are the adverse drug reactions of fenofibrate?

Answer 23

cholelithiasis (gall stones), GI upset, myositis (muscle weakness)

Question 24

what are the contraindications of fenofibrate?

Answer 24

photosensitivity, gall bladder disease

Question 25

what are the drug interactions of fenofibrate?

Answer 25

warfarin - increases anticoagulation

Question 26

what drug class is ezetimibe?

Answer 26

cholesterol absorption inhibitor

Question 27

what is the mechanism of action of ezetimibe?

Answer 27

• Inhibit NPC1L1 transporter at brush border of the small intestine
• Reduces absorption of cholesterol by the gut ~50%
• Hepatic LDL receptor expression increases
• ↓total cholesterol ~ 15%, LDL ~ 20%

Question 28

what are the pharmacokinetics of ezetimibe?

Answer 28

Pro-drug
hepatic metabolism -> enterohepatic circulation -> limits systemic exposure as stays in GI
secreted by bile

Question 29

what are the indications for ezetimibe?

Answer 29

Adjunct to statin (or if not tolerated?) for homozygous familial hypercholesterolemia

Question 30

what are the adverse effects of ezetimibe?

Answer 30

abdominal pain

GI upset

Question 31

what are the contraindications of ezetimibe

Answer 31

hepatic failure

Question 32

what is the target cholsterol for secondary prevention?

Answer 32

2.0 mmol/L LDL cholesterol is a target → ~ 4.0 mmol/L total

Question 33

why is ezetimibe used in multiple target therapy?

Answer 33

Combination of ezetimibe with statin benefit in CKD and in some for secondary CVD prevention. evidence shows decrease in major CV event

Question 34

what drug class is alirocumab?

Answer 34

PCSK9 inhibitor (monoclonal antibody)

Question 35

what is the mechanism of action of alirocumab?

Answer 35

inhibits PCSK9 protein.
When LDL attaches to LDL receptor, receptor is internalised. LDL catabolised and receptor degraded or recycled in cell
PCSK9 – protein that binds internalised LDL-R – directing for degradation
PCSK9 inhibitors demonstrated highly significant reduction in LDL cholesterol over placebo (statin +/- ezetimibe)

Question 36

what are the disadvantages of PCSK9 inhibitors?

Answer 36

Long term effects on cholesterol lowering and CVD risk remain to be determined
Lifetime injections - could affect adherence
very expensive

Question 37

what are the indications of alirocumab?

Answer 37

currently recommend for primary and secondary prevention in resistant familial
hypercholesterolemia and some high risk secondary prevention patients

Question 38

Other than medication, what can patients do to reduce cholesterol?

Answer 38

Exercise
Plant sterols provide some LDL cholesterol lowering effects
Naturally occurring in grains, legumes etc. structurally similar to cholesterol – competing for
absorption
• Work with statins but not with ezetimibe
• Yes to….
Fish oils/oily fish
Fibre, whole grains
Vitamin C/E
• Alcohol – increases HDL cholesterol BUT also increases triglycerides

Question 39

Which statin is offered as a first line option to patients in the UK and why?

Answer 39

Atorvastatin - has high efficacy compared to other statins such as simvastatin. Has lowest number needed to treat of statins. The Number Needed to Treat (NNT) is the number of patients you need to treat to prevent one additional bad outcome (death, stroke, etc.).

Question 40

How does ezetimibe reduce circulating cholesterol?

Answer 40

Ezetimibe inhibits NPC1L1 in the small intestine to prevent cholesterol absorption. As absorption is decreased there is less circulating cholesterol. It also increases the heptic expression of the LDL receptor to remove LDL from circulation

Question 41

How do PCSK9 inhibitors work?

Answer 41

inhibit the PCSK9 protein which marks the LDL receptor for degredation once it has bound to LDL. Inhibiting this protein stops the receptor from being degraded and increases its expression, effectivelt reducing the amount of circulating LDL.

Question 42

Why may it be appropriate to prescribe a statin and ezetimibe together, comment on their
mechanisms?

Answer 42

statin reduces the amount of intracellular cholesterol produced by competitively inhibiting the HMG-CoA reductase to reduce the HMG-CoA to mevalonic acid.
ezetimib reduces the cholesterol absorption from the small inestine and increases the removal of LDL from circulation
As their mechanisms focus on different pathways, they can be effectively used together in multiple target therapy to reduce the risk of a CV event

Question 43

What considerations should be made when prescribing a statin for primary CVD prevention?

Answer 43

individual patient risk/benefit

Full lipid profile including HDL, and non-HDL + triglycerides before prescribing

Question 44

What action of other drugs is important to consider when prescribing a statin which may influence the dose of the statin prescribed?

Answer 44

amlodipine interacts with simvastatin
The metabolism of statins is reduced by cytochrome P450 interactions inhibitors, such as amiodarone, diltiazem, itraconazole, macrolides and protease inhibitors. This leads to accumulation of the statin in the body, which may put patients at increased risk of adverse effects.
Amlodipine has a similar interaction although the mechanism is less clear. To reduce this risk you may need to reduce the dose of the statin or, if the other drug is being used for a short period only (e.g. a course of clarithromycin therapy), withhold the statin.