4.1.2 Hyperlipidaemia and Fibrates Flashcards
What is an example of a fibric acid derivative (fibrate)?
Fenofibrate
What is the mechanism of action of fibrates?
Activation of nuclear transcription factor PPARa (peroxisome proliferation-activated receptor)
PPARa regulates expression of genes for lipoprotein lipase; increases lipoprotein lipase
What does an increase of lipoprotein lipase lead to?
Increased triglyceride removal from lipoprotein in plasma
Increased fatty acid uptake by liver
Increased HDL levels
Increased LDL affinity for receptor
When are fibrates used?
Rarely used alone
Co-prescribed in mixed hyperlipidaemias
Adverse effects of fibrates?
GI upset
Myositis
Cholelithiasis
When should you not give fibrates?
Photosensitivity
Gall bladder disease
Important drug interactions of fibrates
Warfarin, increases anticoagulation
What is an example of a cholesterol absorption inhibitor?
Ezetimibe
How do cholesterol absorption inhibitors work?
- 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%
How are cholesterol absorption inhibitors metabolised?
Pro-drug
Hepatic metabolism, enters enterohepatic circulation and recycled by GI and liver, reducing systemic exposure
Secreted by bile
When are cholesterol absorption inhibitors used?
Adjunct to statin, or if statins cannot be tolerated for familial patients
Adverse effects of cholesterol absorption inhibitors
Abdominal pain
GI upset
Angioedema
Do not give cholesterol absorption inhibitors?
Hepatic failure
Important drug interactions of cholesterol absorption inhibitors?
Mindful if given with statins, increased risk of rhabdyomyolysis
How is ezetimibe taken?
10mg once per day, does not change
Why is ezetimibe given with statins?
Benefical in CKD, allows you to use a lower dose of statins and in some for secondary CVD prevention
What additives may be given in familial hypercholesterolaemia?
Fibrates or nicotinic acid, not for primary or secondary prevention of CVD
Target cholesterol levels for those being treated in secondary prevention?
1.8mmol/L LDL-C
< 2.5mmol/L non-HDL-C
What has dual therapy with simvastatin and ezetimibe been shown to do?
Decreases CV event rates better than statins alone
Asides from statins and cholesterol absorption inhibitors, what else is available for lowering cholesterol?
PCSK9 inhibitors
siRNA
What does PCSK9 do?
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
What are two examples of PCSK9 inhibitors?
Alirocumab
Evolocumab
-cumab suffix
How do PCSK9 inhibitors work?
Monoclonal antibodies prevent binding of PCSK9 to LDL-R, thus reducing LDL-R degradation
Give an example of siRNA
Inclisiran
How does siRNA work?
Inhibits hepatic translation of PCSK9
Decreases PCSK9 production
What is the cost of statins vs targeting PCSK9?
50x the cost, requires lifetime injections
Currently only recommended when other treatments haven’t worked
What has been shown to also block PCSK9?
Caffeine
What natural options have been shown to lower cholesterol?
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
Why do plant sterols work with statins but not ezetimibe?
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
What is the cost effectiveness of statins?
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
