Session 5 Hyperlipidaemias

Question 1

Why is cholesterol important?

Answer 1

Essential for membrane integrity

It is a precursor in production fo steroid hormones, bile acids and vitamin D

Question 2

Cholesterol is a modifiable risk factor for CVD. Describe the relationship between cholesterol and morbidity/mortality from coronary heart disease

For every 1 mmol/L total cholesterol reduction, what happens to CVD risk?

Answer 2

Relationship between elevated cholesterol and CHD mortality and morbidity

Reduction in total cholesterol of 10% affords 15% reduction in CHF mortality and 11% in total mortality

LDL cholesterol lowering is the target for CVD prevention

For every 1 mmol/L reduction of total cholesterol there is around 20% decrease of CVD risk

Question 3

Statins

Drug names?

Answer 3

Atorvastatin

Simvastatin

Question 4

Statins

MoA

Answer 4

Competitive inhibition of HMG-CoA reductive (which is a rate controlling enzyme in mevalonate pathway)

Leads to up-regulation of hepatic LDL receptors

Increased clearance of circulating LDL

Question 5

Other than increased clearance of circulating LDL’s, what are the additional benefits of Statins?

Answer 5

• improved vascular endothelial function
  (Increase NO and decrease endothelin)
• stabilisation of atherosclerotic plaque
  (Decrease smooth muscle cell proliferation and increase collagen)
• improved haemostasis
  ( decrease plasma fibrinogen and platelet aggregation but increase fibrinolysis)
• anti-inflammatory
  ( decrease proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines - all decrease!)
• antioxidant
  (Decrease superoxide formation)

Question 6

Prescribing considerations for

Simvastatin

Atorvastatin

Half life?

Answer 6

Simvastatin = prodrug that is activated by first pass metabolism PLUS short half life (2 hours) 
Atorvastatin = first pass metabolism active derivatives PLUS long half life (over 30 hours)

Question 7

Warnings/side effects of statins

Answer 7

GI disruption
Nausea and headache
Myalgia (normally dose related)
Rhabdomyolysis (rare)

Question 8

Contraindications - Statins

Answer 8

Renal impairment
Pregnancy and breastfeeding

CYP 34A important

Question 9

Primary prevention (10 year CV risk of >10%)?
Secondary prevention?

Answer 9

20 mg atorvastatin once daily

80 mg atorvastatin once daily

Need to do a full lipid profile before prescribing!

• avoid grapefruit juice
• take at night

Question 10

What do fabric acid derivatives do?

Name?

Answer 10

They activate a nuclear transcription factor = PPAR alpha which regulates the expression of genes that control lipoprotein metabolism so increase the production of lipoprotein lipase

Name = fenofibrate

Question 11

What is the effect of increased production of lipoprotein lipase have?

Answer 11

Increased triglycerides from lipoprotein in plasma

Increased fatty acid uptake by the liver

Increased levels of HDL

Increased LDL affinity for receptor

Question 12

Side effects of fibrates?

Contradictions?

Answer 12

Side effects = cholelithiasis (gall stones) and myositis (inflammation of muscles)

Contradictions = warfarin

Question 13

What do cholesterol absorption inhibitors do / how do they act?

Answer 13

Inhibit NPC1L1 transporter

Reduces absorption of cholesterol by the gut by around 50%

Hepatic LDL receptor expression increases

Decrease in total cholesterol by about 15%
Decrease in LDL cholesterol by about 20%

Question 14

Name of a cholesterol absorption inhibitor?

Answer 14

Ezetimibe

Question 15

Metabolism of cholesterol absorption inhibitors? E.g. ezetimibe

Answer 15

Pro-drug
Hepatic metabolism —> enterohepatic circulation

Limits systemic exposure

Sequestered by bile so good tolerability and replaced most resins and sequestrants

Question 16

Side effects and contradictions of cholesterol absorption inhibitors?

Answer 16

Side effects

• abdominal pain
• GI upset

Contradictions
* hepatic failure

Question 17

How do PCSK9 inhibitors work?

Answer 17

PCSK9 is a protein that binds internalised LDL-R, directing it for degradation

So PCSK9 inhibitors significantly reduce LDL cholesterol

Question 18

Name of PCSK9 inhibitors?

Answer 18

Alirocumab

Evolocumab

Question 19

Why might it be appropriate to prescribe statin an ezetimibe (cholesterol absorption inhibitor) together?

Answer 19

There is no dose escalation with ezetimibe

Combination with statin has a benefit in CKD and secondary CVD prevention

Good to combine these two in people that can only tolerate a low dose of statin

Question 20

What are the non-pharmaceutical methods of trying to reduce cholesterol?

Answer 20

Diet!

• plant sterols provide LDL cholesterol lowering effects
• plant sterols are naturally occurring in grains, legumes etc
• plant sterols have a similar structure to cholesterol so compete with it for absorption

Good things to include in diet

• fish oils and oily fish
• fibre and whole grains
• vitamin C and vitamin E

Alcohol = increases HDL cholesterol BUT also increases triglycerides

Question 21

What is the cost-effectiveness of treating high cholesterol?

Answer 21

Numbers needed to treat are relatively small

Economic considerations significant in decision to lower 10 year CVD risk to >10%

Cost increases as baseline risk of patient falls