Hyperlipidaemias Flashcards
How does cholesterol enter the body?
- Most synthesised in body
- ~25% contributed by diet
Why is cholesterol essential in the body?
- Membrane integrity
- Precursor in production of steroid hormones
- Bile acids
- Vitamin D
Why is LDL considered to be bad cholesterol?
- Susceptible to oxidation at damaged endothelium
- ROS contributes to endothelial dysfunction
- Increases adherence of lipid rich deposits
- Foam cells formed (precursor to atheromatous plaques)
Which type of cholesterol is considered good?
- HDL
- Carries cholesterol away from circulation
- To tissues that require it
- To liver for disposal in bile
What blood tests can be done to assess CHD?
- Total blood cholesterol
- Now non-HDL cholesterol is a more reliable measure
Why is cholesterol targeted to reduce CVD risk?
- Modifiable risk factor, like BP (other than genetic predisposition)
- Data shows relationship between elevated cholesterol and morbidity and mortality from CHD
- Reducing cholesterol by 10% affords ~15% reduction in 10 year CHD mortality and ~11% reduction in total mortality
How do we determine how aggressively to treat high cholesterol?
- Take total CVD risk into account
- Patient’s willingness to take medication and modify lifestyle
- Familial forms of hypercholesterolaemia have specific/focused targets
Outline CVD risk
- Additive
- Multifactorial
How does high cholesterol affect blood vessels?
- Causes fatty streaks
- First develop in adults aged 20-29
What is the mechanism of action of statins?
- Competitive inhibition of HMG-CoA reductase
- Leads to decreased concentration of cholesterol within cells
- Stimulates synthesis of LDL receptors
- Increased number of LDL receptors promotes uptake of LDL from blood
- Low intracellular cholesterol decreases secretion of VLDL
What are the additional benefits of statin therapy?
- Improved vascular endothelial function
- Stabilisation of atherosclerotic plaque
- Improved haemostasis
- Anti-inflammatory
- Antioxidant
How does statin therapy improve vascular endothelial function?
- Increased NO
- Increased vascular endothelial growth factor
- Decreased endothelin
How does statin therapy improve stabilisation of atherosclerotic plaques?
- Decreased smooth muscle cell proliferation
- Increased collagen
How does statin therapy improve haemostasis?
- Decreased plasma fibrinogen
- Decreased platelet aggregation
- Increased fibrinolysis
How does statin therapy act as an anti-inflammatory?
- Decreased proliferation of inflammatory cells into plaque
- Decreased plasma CRP
- Decreased adhesion molecules and cytokines
How does statin therapy act as an antioxidant?
- Decreased superoxide formation
Name some kinds of statin
- Simvastatin
- Atorvastatin
What prescribing considerations need to be made with statins?
- Simvastatin is a prodrug activated by first pass metabolism - half life is 2h
- Atorvastatin - active derivatives obtained by first pass metabolism - half life is 24h
What are the adverse effects of statins?
- GI disruption
- Nausea
- Headache
- Myalgia (dose related)
- Rarely - rhabdomyolysis
- Increased liver enzymes
What are the contraindications for statins?
- Renal or hepatic impairment
- Pregnancy (cholesterol important for foetal development)
- Breastfeeding
What are the DDIs of statins?
- Anything that is also metabolised by CYP 3A4
- Raises plasma statin concentration
- Because other compounds are metabolised by CYP 3A4 instead of statins
- E.g. amiodarone, diltiazem, macrolides, amlodipine, grapefruit juice
- May be appropriate to withhold statin short-term whilst taking other agents
How do we decide which statins to use?
- Dose dependant reduction in LDL-cholesterol for all
- Cost and side effect severity has driven prescribing choices
- Atorvastatin and simvastatin are relatively cheap and easily accessible
What is the recommended dose for primary prevention of CVD?
- 20 mg atorvastatin once daily
- Given to patients with 10 year risk of CVD greater tan 10%
- Incorporate individual patient and risk/benefit discussions
What is the recommended dose for secondary prevention of CVD?
- 80 mg atorvastatin once daily
What other steps need to be taken before prescribing statins?
- Full lipid profile
- Includes HDL and non-HDL and triglycerides
What is the target when prescribing statins?
- Broadly >40% reduction in non-HDL cholesterol at 3 months
Why is simvastatin taken at night?
- Has a relatively short half life
- LDL receptor synthesis and activity are much greater at night
- Drug is most effective at night when plenty of receptors are active
What nocebo effect is associated with taking statins?
- Muscle pain
- Big challenge to adherence
- Leads patients to decrease or stop use of statins
- Makes patients reluctant to even begin taking statins as they are aware of the potential side effects
What is the mechanism of action of fibrates?
- Activate PPARa
- Nuclear transcription factor that regulates expression of genes controlling lipoprotein metabolism
- Increase production of lipoprotein lipase
- Increases triglyceride removal from lipoproteins in plasma
- Increase fatty acid uptake by liver
- Increase levels of HDL
- Increase LDL affinity for receptor
How are fibrates prescribed?
- Co-prescribed with statins
- In mixed hyperlipidaemias
What are the adverse side effects of fibrates?
- GI upset
- Myositis
- Gall stones
What are the contraindications of fibrates?
- Photosensitivity
- Gall bladder disease
What are the DDIs of fibrates?
- Warfarin
- Causes increased anticoagulation
Give an example of a fibrate
- Fenofibrate
What is the mechanism of action of cholesterol absorption inhibitors?
- Inhibit NPC1l1 transporter at brush border in small intestines
- Reduces absorption of cholesterol by gut
- Hepatic LDL receptor expression increases
- Decreases total cholesterol by ~15%
- Decreases LDL cholesterol by ~20%
How are cholesterol absorption inhibitors metabolised by the body?
- Pro-drug
- Hepatic metabolism
- Enter enterohepatic circulation for recycling
- Limits systemic exposure
- Secreted by bile
How are cholesterol absorption inhibitors prescribed?
- Adjunct to statins
- Beneficial in CKD and for secondary CVD prevention
- Cannot escalate dose of ezetimibe
- Useful in patients who can only tolerate a low dose of statins
What are the adverse side effects of cholesterol absorption inhibitors?
- Abdominal pain
- GI upset
- Angioedema
What are the contraindications of cholesterol absorption inhibitors?
- Hepatic failure
What are the DDIs of cholesterol absorption inhibitors?
- Need to be mindful if prescribed with a statin
- Theoretical increased risk of rhabdomyolysis
In which patients might we consider adding fibrates or nicotinic acids alongside statins?
- Patients with familial hypercholesterolaemia
- Not given to patients for primary/secondary prevention of CVD
What is the mechanism of action of monoclonal antibodies designed to treat high cholesterol?
- Inhibits PCSK9
- PCSK9 signals that LDL receptors should be internalised for degradation
- Inhibition increases uptake of LDL cholesterol into cells
Why are monoclonal antibodies not commonly prescribed?
- Very expensive
- Long term effects yet to be determined
- Requires lifelong injections every 3-6 months
Give some examples of monoclonal antibodies that treat high cholesterol?
- Alirocumab
- Evolocumab
What is the mechanism of action of inclisiran?
- Inhibits hepatic translation of PCSK9
- Very newly available to some in primary care e.g. patients with genetic causes of hypercholesterolaemia
What non-medicinal options can help lower cholesterol?
- Plant sterols (occur naturally in grains, legumes etc)
- Fish oils/oily fish
- Fibre, whole grains
- Vitamin C and E
