Lipid-Lowering Drugs

Question 1

What is the main aim in lipid lowering?

Answer 1

LDL reduction by lifestyle and diet change, lipid lowering drugs

Question 2

Dietary benefit examples in lowering LDL

Answer 2

Soluble fibre in diet eg oat bran, fruit veg (2-8g/day)
Soy protein (20-30g/day)
Stanton esters (1.5-4g/day) to inhibit cholesterol absorption

Question 3

Drugs in common use to reduce lipids

Answer 3

HMG-CoA reductase inhibitors (statins)
Fibrates
Ezetimibe
Colesevelam
Omega-3 fish oil
PCSK-9 inhibitors
New Drugs - Bempedoic acid; inclisiran

Question 4

Describe the mechanism of action of statins

Answer 4

HMG CoA reductase inhibitors - competitively inhibit the activity of HMG CoA reductase, the rate limiting enzyme in cholesterol synthesis
Causes a transient modest decrease cellular cholesterol concentration
The decr in cellular cholesterol activates sterol regulatory element binding protein (SREBP), a transcription factor, that up regulates the gene encoding for the LDL receptor
Increased LDL-receptor expression (70% in hepatocytes) increases uptake of plasma LDL thus decreasing plasma LDL conc

Question 5

Non-cardiovascular harms and benefits of statins

Answer 5

Muscle pain - Rhabdomyolysis; Myostis; Myalgia
Diabetes - modest increase in incidence especially higher intensity statins
Liver - modest increase in ALT, asymptomatic, reversible and more common with high intensity statins
Cataracts - no robust evidence but “healthy participant” and prescription bias i.e. these patients more likely to take statins and less likely to develop medical problems (confounding)
Cognition - memory loss no robust evidence
AKI - association may be due to confounding by indication i.e. sicker patients receive the high dose statins
OTHERS: Possible link with COPD, pulmonary fibrosis, pancreatitis, fatigue, erectile dysfunction, cancer (evidence not robust)
SUMMARY: Benefits of statins outweigh harms

Question 6

Primary mode of action of fibrates

Answer 6

By activating the nuclear transcription factor PPAR alpha especially in liver and muscle

Question 7

Describe fibrates action and result

Answer 7

Modulation of target genes increases activity of lipoprotein lipase and decrease synthesis of apo C-111 → ↓ VLDL and ↓ triglycerides
ALSO ↓ liver fatty acid oxidation (↓ VLDL) and promote shift in density of LDL to more buoyant particle (less atherogenic)
RESULT:
1. ↓ triglycerides 30-50%
2. ↑high density lipoprotein 5-15%

Question 8

Side effects of fibrates combined with statins in patients with diabetes and hypertriglyceridemia

Answer 8

Increased risk of myosotis when combined with statin risk increases with renal impairment (reduce dose)
Gastrointestinal disturbance, cholestasis, headache, dizziness, weight gain
Evidence of additional CVD protection is minimal

Question 9

Side effects of ezetimibe

Answer 9

GI disturbance, headache, fatigue, myalgia,

Question 10

What is colesevelam

Answer 10

Bile acid sequestrant

Question 11

Describe PCSK-9 inhibitors

Answer 11

Monoclonal antibodies against pro protein convert are subtilising-like/Kexin-9
Names: evolocumab, alirocumab
Fortnightly or monthly subcutaneous injection
Adverse effects - nasopharyngitis, back pain, flu-like symptoms

Question 12

When is Inclisiran recommended

Answer 12

Only if:
Secondary prevention
LDL-C persistently at least 2.6mmol/L
The company provides inclisiran according to the commercial arrangement

Question 13

What is inclisiran

Answer 13

A small-interfering RNA (siRNA)
Injection site reactions

Question 14

When is bempedoic acid recommended

Answer 14

Statins are contraindicated or not tolerated
Enzetimibe alone does not control LDL cholesterol well enough
The company provides bempedoic acid and bempedoic acid with ezetimibe according to the commercial arrangement

Question 15

Atherosclerosis does not progress when LDL is….

Answer 15

<1.73mmol/L

Question 16

More effective LDL-C lowering …..

Answer 16

Improves patient outcomes
All cause death or major CV events in all randomised subjects

Question 17

What does pravastatin 40mg do for LDL

Answer 17

Median LDL-C reduction 10%
LDL-C achieved 2.5mmol/l
Event rate 26.3%

Question 18

What doe s atorvastatin 80mg do for LDL

Answer 18

Median LDL-C reduction 42%
LDL-C achieved 1.6mmol/L
Event rate 22.4%

Question 19

Describe the IMPROVE-IT trial

Answer 19

• Used simvastatin or simvastatin + ezetimibe post acute coronary syndrome
• The combination group had better cholesterol reduction and had a modest reduction in cardiovascular events
• It is probably cholesterol-lowering rather than statin therapy that is important

Question 20

What is the ‘optimal’ LDL cholesterol

Answer 20

Around 1.0mmol/l or less

Question 21

What is the optimal control of hyperlipidaemia

Answer 21

Statin first line for overwhelming majority of patient
Consider fibrates first one if triglycerides >5.0mmol/l