Lipoprotein disorders and management

Question 1

5 main classes of lipoproteins in order of density (most to least)

Answer 1

1. High density lipoproteins (HDLs)
2. Low density lipoproteins (LDLs)
3. Intermediate density lipoproteins (IDLs)
4. Very low density lipoproteins (VLDL)
5. Chlyomicrons

Density determined by the amount of lipid per particle

Question 2

What is plasma triglyceride and cholesterol transported by

Answer 2

Most plasma triglyceride(TG) is transported in chylomicrons and VLDLs; most plasma cholesterol is carried as cholesteryl esters in LDLs and HDLs.
The cholesterol in LDL accounts for over half of the plasma cholesterol in most individuals.

Question 3

Apolipoproteins- proteins associated with lipoproteins and required for assembly, structure and function of lipoproteins. Activate enzymes important for lipoprotein metabolism and act as ligands for cell surface receptors. List the subtypes

Answer 3

ApoA-I: synthesised in the liver and intestine; found in virtually all HDL particles

ApoA-II: second most abundant HDL apolipoprotein and is on approximately 1/3rd of all HDL particles

ApoB: major structural protein of chlyomicrons, VLDLs, IDLs and LDLs

ApoE: present in multiple copies on chylomicrons, VLDL and IDL and plays a crucial role in the metabolism and clearance of TG-rich particles.

Question 4

Effect of LDL levels on CAD

Answer 4

Majority of serum cholesterol is transported in LDL-C and therefore the relationship is similar for LDL and CAD
Risk of coronary heart disease rises steeply at higher LDL-C concentrations (non-linear relationship)

Question 5

HDL and triglycerides relationship to CAD

Answer 5

Below average HDL-C (usually in combination with elevated TG) is associated with increased risk of coronary heart disease.

More atherogenic and associated with increased cardiac events, increased insulin resistance and hyper-viscosity.

Question 6

Main treatment target lipid in CVD

Answer 6

LDL-C is recommended as the primary target for treatment. TC should be considered as the treatment target if other analyses are not available.
HDL not recommended as a target

Question 7

Lipid targets:
Very high risk
- established CVD, DM with end organ damage or T2DM >40yr + 1 other RF, mod-severe CKD or SCORE ≥10 %)

Answer 7

<1.8 OR a ≥ 50 % LDL-C reduction if baseline 1.8-3.5

Question 8

High risk

• DM not above
• elevated risk factors, SCORE ≥5 - <10%
• FHx

Answer 8

<2.5 OR a ≥ 50 % LDL-C reduction if baseline 2.6-5.2

Question 9

Low to Moderate risk

- SCORE level >1 to ≤5%

Answer 9

<3.0

Question 10

Lipid Targets - HDL

Answer 10

No targets, but >1 in Men and >1.2 in women indicates lower risk

Question 11

Lipid Targets - TG

Answer 11

No target, but <1.7 indicates lower risk and higher levels indicates a need to look for other risk factors

Question 12

Secondary lipid targets

Non-HDL-C

Answer 12

<2.6 mmol/L and <3.4 mmol/L in subjects at very high and high total CV risk, respectively

Question 13

Secondary lipid targets

ApoB

Answer 13

<80 mg/dL and <100 mg/dL in those at very high and high total CV risk, respectively

Question 14

General targets for people on lipid lowering therapy

Answer 14

LDL-C <2
Triglycerides <2
non-HDL-C <2.5
Total Cholesterol <  4
HDL-C >1

Question 15

Hypertriglyceridaemia therapy

Answer 15

In particular high-risk patients lowering of high TG by using fibrates is recommended. Nicotinic acid, nicotinic acid+laropiprant, n-3 fatty acids, should be considered as well as statin + fibrate or nicotinic acid . The combination of the above considered drugs with n-3 fatty acids may be considered.

Question 16

Hypercholesterolaemia therapy

Answer 16

If drug treatment is indicated to decrease LDL-C, a statin is recommended, up to the highest tolerable dose, to reach the target level.
If the target level is not reached, statin combination with a cholesterol absorption inhibitor or bile acid sequestrant or nicotinic acid may be considered.

Question 17

ACS lipid target

Answer 17

In patients with an ACS, the recommendation is with high-intensity statin ‘atorvastatin 80mg’, with an aim of LDL<1.8 AND regardless of what baseline LDL levels are.

Question 18

Possible indications for treatment of isolated hypertriglyceridemia

Answer 18

Overt CVD, a strong family history of CVD, and multiple coexisting cardiac risk factors.
There is an increased risk of muscle toxicity in patients taking some fibrates and a statin

Question 19

Statins: MOA, main side effect, affect on LDL, HDL and TG

Answer 19

Competitive inhibitors of HMG-CoA reductase, which is the rate-limiting step in cholesterol biosynthesis

o ¯ Total Cholesterol by 20-30%
o ¯ LDL by ~30%
o ¯ TG by 10-20%
o inc. HDL by 5-10%

Absolute risk reduction is most significant in secondary prevention

Headache; N; sleep disturbance
Increased LFTs.
Myositis and rhabdomyolysis, primarily
when given with gemfibrozil or cyclosporine; or with severe renal insufficiency (CrCl <30 mL/min).

Lovastatin, atorvastatin, rosuvastatin, and simvastatin potentiate effect of warfarin Most statins can also affect digoxin metabolism and levels
Check baseline LFTs, TSH and CK

Question 20

Fibrates: MOA, main side effect, affect on LDL, HDL and TG

Answer 20

Gemfibrozil and fenofibrate:
These mediations stimulate peroxisome proliferator active receptor alpha (PPAR alpha) – a nuclear receptor that controls the genes mediating triglyceride metabolism
Reduces hepatic synthesis of fatty acids and triglyceride rich lipoproteins (VDLD)
Stimulation of lipoprotein lipase thus promoting triglyceride catabolism and HDL production
Increases synthesis of apolipoprotein A1
Overall effects reduce TG by 50% and increase HDL-C by 20% (without significant changes in LDL-C)
Gemfibrozil contraindicated with statins and potentiates warfarin action
Fenofibrates dose reduced in renal failure, can cause skin rash and GI upset

Question 21

Nicotinic acid: MOA, main side effect, affect on LDL, HDL and TG

Answer 21

• Inhibits synthesis of VLDL by liver
• Also inhibits breakdown of HDL
• Unclear mechanism, ? related to inhibiting apo-B100 or promoting LPL
• HDL by approx 25%, ¯ LDL by 15-18% and TG by 20-40%
unique that it lowers Lp(a) levels by 30%

Question 22

Cholestyramine: MOA, main side effect, affect on LDL, HDL and TG

Answer 22

Binds bile salts in the gut – lowering LDL-C without significant effects on HDL-C or TG (may slightly TG)
• Limited by side effects – nausea, reflux

Question 23

Ezetimibe: MOA, main side effect, affect on LDL, HDL and TG

Answer 23

Inhibits intestinal absorption of cholesterol by interaction with the intestinal mucosal transporter NPC1L1 (Niemann-Pick type C1 like 1 protein) that absorbs dietary and biliary cholesterol
Reduces LDL-C by 10-15% (marginal beneficial effects on HDL and TG)
Used only in combination with statin

S/E Deranged LFTs

Question 24

Neomycin: MOA, main side effect, affect on LDL, HDL and TG

Answer 24

Ototoxic and nephrotoxic - reduced LDL 25-30%

Question 25

PSCK9 inhib: MOA, main side effect, affect on LDL, HDL and TG

Answer 25

The enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces the number of receptors available to bind with LDL cholesterol.
• Inhibitors of this enzyme therefore increase the number of receptors. This results in more LDL cholesterol being removed from the circulation

Fourier trial
o Decreased non-fatal MI, stroke, coronary revascularisation by 20%
o Mean LDL 0.78
o No decrease in CV or overall mortality
• Dose: subcutaneous injection and it can be injected every two weeks or once a month
• Indications (PBS) for Evolucumab
o Familial homozygous hypercholesterolaemia

Question 26

Omega-3 fatty acids: MOA, main side effect, affect on LDL, HDL and TG

Answer 26

High daily doses (2-5g) lower TG levels by up to 50% (without significant effects on LDL-C or HDL-C)
• Platelet aggregation is also inhibited by fish oil

Question 27

Inherited Triglyceride disorders

Answer 27

1) Familial hypertriglyceridemia
Clues to diagnosis:
– pancreatitis
– retinal vein thrombosis
2) Lipoprotein lipase deficiency.
Clues to diagnosis:
– presents in childhood with eruptive xanthomas, lipaemia retinalis.
– TG does NOT improve after FFP
3) Apoprotein C deficiency:
Clues to diagnosis:
– TG improves after FFP.
First line treatment for Hypertriglyceridemia is Fibrates

Question 28

inherited cholesterol disorders

Answer 28

1) Heterozygous familial hypercholesterolemia.
Clues to dianosis:
– typical family history of early CVD.
– tendon xanthomas.
– genetic defect is LDL receptor.
2) Homozygous familial hypercholesterolemia-rare
3) Apoprotein B100 gene mutation
4) Polygenic hypercholesterolemia
First line treatment is with statins +/- ezetimibe.

Question 29

Inherited HDL disorder

Answer 29

– Tangier disease- due to ABC1 gene mutation.

First line treatment is fibrates.