Session 5: Hyperlipidaemias

Question 1

Broad functions of cholesterol.

Answer 1

Membrane integrity (both fluidity and rigidity)

Precursor of steroid hormones

Bile acids

Also important for vitamin D production in dermis.

Question 2

What is LDL?

Answer 2

Lipoprotein carrying cholesterol.

It is susceptible to oxidation at damaged endothelium by necrotic tissue and ROS leading to atherosclerosis.

This is because LDL has a higher half-life.

Question 3

Function of HDL.

Answer 3

Carries cholesterol away from circulation to the liver for recycling.

Question 4

Healthy level of:

Total cholesterol

LDL

Non-HDL

HDL

TAGs

Answer 4

<5 mmol/l

<3 mmol/l

<4 mmol/l

>1 mmol/l

<2.3 mmol/l

Question 5

Briefly explain the formation of atheroma by LDL.

Answer 5

Accumulation of LDL will be oxidised by local endothelial cells.

Recruited monocytes will phagocytose the oxidised LDL via scavenger receptors.

Foam cells form and build up in the intima.

Proliferation of smooth muscle cells and a fatty streak develops.

Question 6

When do fatty streaks start to form?

Answer 6

Early on in life.

1/3 in 20-29 year olds have fatty streaks and just increase in prevalence with age meaning it can start early.

Question 7

Explain the action of statins.

Answer 7

Competitive inhibition of HMG-CoA reductase.

This leads to lower levels of cholesterol as that is the rate-controlling enzyme in the mevalonate pathway.

The low levels of intracellular cholesterol leads to stimulation of hepatic LDL receptors.

This promotes uptake of LDL from blood.

Low intracellular cholesterol also decreases the secretion of VLDL.

Question 8

Examples of statins.

Answer 8

Atorvastatin

Simvastatin

Fluvastatin

Pravastatin

Rosuvastatin

Lovastatin

Question 9

Give additional benefits of statin therapy.

Answer 9

Improved vascular endothelial function (More NO and less endothelin)

Stabilisation of atherosclerotic plaque

Improved haemostasis (less plasmafibrinogen and more fibrinolysis)

Anti-inflammatory - less proliferation of inflammatory cells into the plaque

Anti-oxidant

Question 10

Explain activation of simvastatin.

Answer 10

A prodrug that is activated by first pass metabolism.

Question 11

Explain the activation of atorvastatin.

Answer 11

Active as it is, but also metabolised and have active derivatives. The active derivates is what accounts for most of the action.

Question 12

Half-life of simvastatin.

Answer 12

2 hrs

Question 13

Half-life of atorvastatin.

Answer 13

>30 hrs

Question 14

Side-effects of statins.

Answer 14

GI disruptions, nausea, and headache

Myalgia with diffuse muscle pain where creatine phosphokinase/creatine kinase levels are 10 times above normal limit.

Rhabdomyolysis can occur on very rare occassions.

Question 15

When should you not take statins?

Answer 15

When renally impaired

When pregnant

When breastfeeding

When taking amiodarone, diltiazem, macrolides and amlodipine.

Also don’t give statins short term

Question 16

Why would you not give statins when pregnant?

Answer 16

Because cholesterol is needed in the developing foetus.

Question 17

Why should you not give statins with amiodarone, diltiazem, macrolides or amlodipine?

Answer 17

Because they are CYP3A4 inhibitors which would cause a build up of statins because CYP3A4 is supposed to degrade it.

This leads to an increased risk of side effects.

Question 18

What drives the choice of statin given?

Answer 18

Cost and severity of side effects.

This explains why rosuvastatin isn’t prescribed as much anymore since it has side-effects.

Question 19

Which statin is primary prevention in hyperlipidaemia?

Answer 19

20 mg atorvastatin once daily.

Question 20

When do you start to give statin?

Answer 20

When QRISK >10%

Question 21

Secondary prevention of hyperlipidaemia.

Answer 21

80 mg atorvastatin once daily.

Question 22

When can you not give secondary prevention (80 mg atorvastatin)?

Answer 22

When ADRs show

When they have chronic kidney disease

Question 23

What is needed to be done before prescribing a statin?

Answer 23

A full lipid profile including HDL, non-HDL + TGs.

Question 24

What is the goal of a statin?

Answer 24

A reduction of over 40% in non HDL-C at three months time.

Question 25

What non-medical is not to be taken when on a statin?

Answer 25

Grapefruit juice (CYP3A4 inhibitor) or whole grapefruits.

Question 26

At what time a day is the statin to be taken?

Answer 26

At night due to the circadian rhythm of the LDL receptor synthesis and activity

Question 27

Explain the mechanism of fibric acid derivatives aka **Fibrates**.

Answer 27

Activation of nuclear transcription factor PPARalpha. This receptor regulates the expression of genes that control lipoprotein metabolism. This means that activation of PPARalpha will cause **increased production of lipoprotein lipase**.

Question 28

Give an example of a fibrate.

Answer 28

Fenofibrate

Question 29

Beneficial effects of fibrates.

Answer 29

Increase in triglycerides from lipoprotein in plasma Increased uptake of fatty acid uptake by the liver Increased levels of HDL Increased LDL affinity for receptor.

Question 30

When are fibrates given?

Answer 30

They are rarely given alone and commonly co-prescribed with a statin in the case of statin not being effective enough.

Question 31

Side-effects of fibrates.

Answer 31

Cholelithiasis Myositis

Question 32

When should you not take fibrates?

Answer 32

When on warfarin.

Question 33

Why should you not take fibrates when on warfarin?

Answer 33

Because it will potentiate the effect of warfarin by competing for the binding. This leads to a greater effect of the warfarin and bleeding.

Question 34

Explain the mechanism of cholesterol absorption inhibitors.

Answer 34

Inhibit NPC1L1 transporter. This leads to a **reduction in the absorption of cholesterol by the gut** (around 50%). Also hepatic LDL receptor expression increases. All of this leads to a reduction in **total** cholesterol by around 15% and reduction of LDL by around 20%.

Question 35

Give an example of a cholesterol absorption inhibitor.

Answer 35

Ezetimibe

Question 36

Explain the pharmacokinetics of ezetimibe.

Answer 36

A pro-drug that is activated by hepatic metabolism. It is activated in **Phase II** where the active metabolite is a conjugate with glucuronide. It is involved in the enterohepatic circulation which limits systemic exposure. **Secreted by bile** and then into faeces mainly. Some renal excretion.

Question 37

When is ezetimibe given?

Answer 37

Adjunct to statin In familial hypercholesterolaemia.

Question 38

ADRs of ezetimibe.

Answer 38

Abdo pain GI upset e.g. diarrhoea

Question 39

When not to take ezetimibe.

Answer 39

Hepatic failure

Question 40

Ezetimibe has a no dose escalation, what does this mean?

Answer 40

That you only give one dose. Giving a larger dose will not have any bigger effect.

Question 41

When is ezetimibe co-prescribed with a statin?

Answer 41

Beneficial in CKD to give a desired effect (since ezetimibe is mainly excreted via faeces). Secondary CVD prevention Those that can only tolerate a low dose statin.

Question 42

When are fibrates or nicotinic acid co-prescribed with a statin?

Answer 42

Specialist advice in familial hypercholesterolaemia Not given as primary or secondary prevention.

Question 43

What does synergistic mean?

Answer 43

That two drugs will together have greater effect than the sum of them.

Question 44

What is the target for LDL levels and total cholesterol levels in secondary prevention?

Answer 44

2. 0 mmol/l LDL 4. 0 mmol/l total

Question 45

Explain the mechanism of PCSK9 inhibitors.

Answer 45

When LDL attaches to the LDL receptor the receptor will be internalised by receptor-mediated endocytosis. The LDL is then catabolised and the receptor is degraded or recycled. PCSK9 is a protein that **binds internalised LDL receptor and directs the receptor for degradation.** PCSK9 inhibitors will **inhibit the degradation of the receptor**. This means **more LDL is taken up by the hepatocyte.**

Question 46

Give examples of PCSK9 inhibitors.

Answer 46

Alirocumab Evolocumab

Question 47

Explain why or why not PCSK9 inhibitors could become a replacement for statins.

Answer 47

It is very effective in lowering cholesterol however **long term effects** on cholesterol lowering and CVD risk remain to be determined. It also **requires lifetime injections** The current **cost** is also that of 100x statins

Question 48

When are PCSK9 inhibitors given?

Answer 48

Currently recommended for primary and secondary prevention of **resistant familial hypercholesterolaemia**. Also in some high risk secondary prevention patients.

Question 49

Give other non-medical options of lowering cholesterol.

Answer 49

Plant sterols that will provide LDL cholesterol lowering effects. Fish oils/oily fish Fibres Whole grains Vitamin C/E

Question 50

Where will you find plant sterols?

Answer 50

Grains Legumes

Question 51

Mechanism of plant sterols.

Answer 51

Structurally similar to cholesterol meaning it will compete for absorption.

Question 52

What does plant sterols work with?

Answer 52

Statins but not with ezetimibe

Question 53

Why is the cost of statins so low?

Answer 53

They are off patent meaning anyone can make a statin.

Question 54

How do you assess CVD risk?

Answer 54

Manchester tables Or more commonly now: **QRISK**

Question 55

When do you start giving statins?

Answer 55

When QRISK gives a chance of CVD at \>10%

Question 56

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

Answer 56

Atorvastatin at 20mg daily dose. This is to reduce cholesterol (especially LDL) and to minimise the risk of CVD.