4.1.2 Hyperlipidaemia and Fibrates

Question 1

What is an example of a fibric acid derivative (fibrate)?

Answer 1

Fenofibrate

Question 2

What is the mechanism of action of fibrates?

Answer 2

Activation of nuclear transcription factor PPARa (peroxisome proliferation-activated receptor)

PPARa regulates expression of genes for lipoprotein lipase; increases lipoprotein lipase

Question 3

What does an increase of lipoprotein lipase lead to?

Answer 3

Increased triglyceride removal from lipoprotein in plasma
Increased fatty acid uptake by liver
Increased HDL levels
Increased LDL affinity for receptor

Question 4

When are fibrates used?

Answer 4

Rarely used alone
Co-prescribed in mixed hyperlipidaemias

Question 5

Adverse effects of fibrates?

Answer 5

GI upset
Myositis
Cholelithiasis

Question 6

When should you not give fibrates?

Answer 6

Photosensitivity
Gall bladder disease

Question 7

Important drug interactions of fibrates

Answer 7

Warfarin, increases anticoagulation

Question 8

What is an example of a cholesterol absorption inhibitor?

Answer 8

Ezetimibe

Question 9

How do cholesterol absorption inhibitors work?

Answer 9

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

Question 10

How are cholesterol absorption inhibitors metabolised?

Answer 10

Pro-drug

Hepatic metabolism, enters enterohepatic circulation and recycled by GI and liver, reducing systemic exposure

Secreted by bile

Question 11

When are cholesterol absorption inhibitors used?

Answer 11

Adjunct to statin, or if statins cannot be tolerated for familial patients

Question 12

Adverse effects of cholesterol absorption inhibitors

Answer 12

Abdominal pain
GI upset
Angioedema

Question 13

Do not give cholesterol absorption inhibitors?

Answer 13

Hepatic failure

Question 14

Important drug interactions of cholesterol absorption inhibitors?

Answer 14

Mindful if given with statins, increased risk of rhabdyomyolysis

Question 15

How is ezetimibe taken?

Answer 15

10mg once per day, does not change

Question 16

Why is ezetimibe given with statins?

Answer 16

Benefical in CKD, allows you to use a lower dose of statins and in some for secondary CVD prevention

Question 17

What additives may be given in familial hypercholesterolaemia?

Answer 17

Fibrates or nicotinic acid, not for primary or secondary prevention of CVD

Question 18

Target cholesterol levels for those being treated in secondary prevention?

Answer 18

1.8mmol/L LDL-C
< 2.5mmol/L non-HDL-C

Question 19

What has dual therapy with simvastatin and ezetimibe been shown to do?

Answer 19

Decreases CV event rates better than statins alone

Question 20

Asides from statins and cholesterol absorption inhibitors, what else is available for lowering cholesterol?

Answer 20

PCSK9 inhibitors
siRNA

Question 21

What does PCSK9 do?

Answer 21

Binds internalised LDL-R directing for degradation

If LDL-R is degraded, LDL is not removed from plasma, thus higher levels of LDL in blood

Question 22

What are two examples of PCSK9 inhibitors?

Answer 22

Alirocumab
Evolocumab

-cumab suffix

Question 23

How do PCSK9 inhibitors work?

Answer 23

Monoclonal antibodies prevent binding of PCSK9 to LDL-R, thus reducing LDL-R degradation

Question 24

Give an example of siRNA

Answer 24

Inclisiran

Question 25

How does siRNA work?

Answer 25

Inhibits hepatic translation of PCSK9 Decreases PCSK9 production

Question 26

What is the cost of statins vs targeting PCSK9?

Answer 26

50x the cost, requires lifetime injections Currently only recommended when other treatments haven't worked

Question 27

What has been shown to also block PCSK9?

Answer 27

Caffeine

Question 28

What natural options have been shown to lower cholesterol?

Answer 28

Plant sterols, shown to reduce LDL upto 0.5mmol/L Found in grains, legumes etc. Fish oils Fibre Whole grains Vitamin C/E Alcohol increases HDl but also increases triglycerides

Question 29

Why do plant sterols work with statins but not ezetimibe?

Answer 29

Ezetimibe competes for uptake of cholesterol, plant sterols work in the same way, structurally similar to cholesterol and compete for absorption Statins prevent production of cholesterol

Question 30

What is the cost effectiveness of statins?

Answer 30

Numbers to prevent major CV events is low, 17-20 Statins are off patent,so they are cheap and easy to make Cost increaes if risk of patient is low (if low risk they won't do much for the cost essentially) Huge annual cost associated with CVD, so statins are good