9 Hyperlipidaemias

Question 1

What % CVD risk reduction is there for every 1mmol/L reduction in total cholesterol?

Answer 1

About 20 % reduction in CVD risk

(Fatty streak present from an early age. We need to limit progression early)

Question 2

How do statins work to reduce cholesterol? (remember about 65% of cholesterol synthesised by body and 35% from diet)

Answer 2

1. Competitive inhibition of HMG-CoA reductase
   
   1. = rate controlling enzyme of mevalonate pathway (see diagram)
2. Upregulation of hepatic LDL receptors
   
   1. Increased clearance of circulating LDL

Question 3

Apart from cholesterol reduction, what other health benefits can taking statins have?

Answer 3

Question 4

Name 3 examples of statins:

Answer 4

• Atorvastatin
• Simvastatin
• Rosuvastatin

Question 5

How do simvastatin and atorvastatin differ in terms of half life?

Answer 5

• Simvastatin half-life = about 2 hrs
• Atorvastatin half-life= >30 hrs

Question 6

Give some of the side effects and contraindications for statins (general).

Answer 6

• Side effects:
  
  • GI disruption
  • Nausea
  • Headache
  • Myalgia
• Contraindications:
  
  • Renal impairment
  • Pregnancy
  • Breastfeeding
  • CYP 3A4 required and = affected by: amiodarone, diltiazem, macrolides, amlodipine

Question 7

How do we choose which statin to use?

Answer 7

Dose dependent

Cost? (Rosuvastatiin= most expensive)

Effectiveness

Side effects

Question 8

Why are people who are prescribed statins told to not eat grapefruit?

Answer 8

Substance in grapefruit juice inhibits CYP3A4 (metabolises lots of drugs)

Question 9

Outline how statins should be prescribed in terms of:

• Aims
• Primary prevention
• Secondary prevention
• When to take statins

Answer 9

Aims:

>40% reduction in non HDL-C

Primary prevention:

20mg Atorvastatin once daily

10 yr CVD risk of >10% using QRISK

Secondary prevention:

80mg Atorvastatin once daily

(CKD-20mg )

When to take statins:

Take at night? Circadian rhythms - LDL receptor synthesis/activity

Question 10

How do fibrates (fibric acid derivatives) act to reduce cholesterol? Give 2 contraindications of fibrates.

Answer 10

Increase production of lipoprotein lipase:

• Activation of nuclear transcription factor: PPARa ((peroxisome proliferation-activated receptor)
• PPARa regulates expression of genes that control lipoprotein metabolism

Addition of fibrates or nicotinic acid - specialist advice in familial hypercholesterolemia – not primary or secondary prevention

Question 11

Give an examples of a fibrate.

Answer 11

Fenofibrate

Question 12

Give 2 side effects and 1 important drug interaction for fibrates.

Answer 12

Side effects:

Cholelithiasis (gall stones)

Myositis (inflammation in muscles)

Contraindications:

Warfarin (fenofibrates can increase effect of warfarin)

Question 13

Ezetimibe is a cholesterol absorption inhibitor. How does it work?

Answer 13

• Inhibits NPC1L1 transporter
  
  • Reduce absorption of cholesterol by gut ~50%
    
    • Hepatic LDL receptor expression increases
      
      • cholesterol ~ 15%, LDL ~ 20%

*

Question 14

Why is it beneficial that ezetimibe is a prodrug?

Answer 14

Pro-drug - hepatic metabolism - enterohepatic circulation
Limits systemic exposure
secreted by bile

Question 15

Give 2 side effects and 1 contraindication for ezetimibe.

Answer 15

• Side effects:
  
  • Abdominal pain
  • GI upset
• Contraindications
  
  • Hepatic failure

Question 16

What are thee target levels for LDL cholesterol and total cholesterol when treating as secondary prevention?

Answer 16

2. 0mmol/L LDL cholesterol
3. 0mmol/L total

Question 17

How is ezetimibe it used?

Answer 17

Often used adjunct to statin (think familial hypercholesterolemia)

Those who can only tolerate low dose statin- given addition of ezetimibe

Question 18

How do PCSK9 inhibitors work?

Answer 18

PCSK9 – protein that binds internalised LDL-R – directing for degradation

When LDL attaches to LDL-R , receptor is internalised, LDL catabolised and receptor degraded or recycled in cell

Question 19

Give 2 examples of PCSK9 inhibitors. How do PCSK9 inhibitors compare to statins?

Answer 19

Alirocumab

Evolocumab

Require lifetime injections

Cost 100x statins

Currently only recomended for prevention in resistant hypercholesterolemia and high risk secondary prevention patients

Question 20

What are some other (non-pharmacological) options for reducing cholesterol?

Answer 20

• Plant sterols (naturally occuring in grains, legumes etc)
  
  • Work with statins (not ezetimibe as sterols compete for absorption so acting on similar pathway)
• Yes to: Fish oils/oily fish Fibre, whole grains, Vitamin C/E

Question 21

How do we estimate someone’s CVD risk (what can we use)?

Answer 21

Qrisk calculator

Useful to show patients when trying to encourage a reduction in cholesterol