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lipid lowering therapies Flashcards

1
Q

What do lipoproteins do?

A

They carry fats around the bloodstream

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2
Q

What percentage of cholesterol is carried by LDL?

A

70%

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3
Q

What is Lp(a) concentration determined by and why is it important?

A

It is very atherogenic and it is purely determined by genetics

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4
Q

What are the good bad and ugly lipoproteins (not technical terminology by any means but helps understand better)?

A

Good: HDL

Bad: VLDL, IDL, LDL, Lp(a)

Ugly: IDL, chylomicron remnant, Lp(a)

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5
Q

What is characteristic of the exogenous lipoprotein transport pathway?

A

Chylomicrons which interact with lipoprotein lipase (LPL) forming a chylomicron remnant which interacts with a receptor (apo(e)) on the liver. Chymomycron remnant has a higher percentage of cholesterol compared to triglycerides. Chylomicrons have lots of triglycerides.

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6
Q

Which body parts have Lipoprotein Lipase?

A

Muscles and adipose tissue

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7
Q

What is the endogenous lipoprotein pathway?

A

VLDL interacts with LPL to form IDL which can bind to remnant receptor. Hepatic lipase breaks IDL down into LDL which interacts with LDL receptor to release the cholesterol and triglycerides.

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8
Q

What receptor do VLDL, IDL, and LDL use in the endogenous pathway?

A

Apo(B100)

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9
Q

How can cholesterol be lowered?

A

Lower saturated fats

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10
Q

How can triglycerides be lowered?

A

Low energy and weight loss

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11
Q

How do statins work?

A

Sterol Regulatory Element Binding Protein (SREBP) increases the amount of production of LDL receptors and acts to decrease the liver’s ability to synthesize cholesterol.

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12
Q

Where do lipophilic statins tend to go more often?

A

To the brain and muscles more than hydrophilic statins

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13
Q

What P450 can we find on Atorvastatin?

A

3A4 (important to know)

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14
Q

What P450 receptor is present on Rosuvastatin?

A

2C9 (limited)

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15
Q

What do statins do?

A

They can effectively reduce LDL-cholesterol

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16
Q

How do LDL -C levels correlate with CHD events?

A

Lower LDL levels are associated with lower percentage of CHD events.

1mmol/L reduction in LDL-c = 22% reduction in CVD risk irrespective of starting LDL-c concentration

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17
Q

What are the hepatic side effects of statins?

A

Mild increase in transaminase (0.5 - 3%)

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18
Q

What are the cognitive side effects of statins?

A

Memory lass (rare)

Others suggest may prevent dementia

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19
Q

What do statins do to diabetes risk?

A

9% increase and linked to HMG CoA reductase

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20
Q

What are statin side effects on muscle injury?

A

Myositis (rare <5/1000)

Dose dependent

Hydrophilic statins don’t enter muscles much

P450 interactions are important for this

Pre-existing conditions such as neuromuscular and endocrine conditions

Ethnicity (chinese people interact negatively with fibrates)

No increase with exercise but CK is higher

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21
Q

How does ezitimibe reduce cholesterol?

A

By decreasing the reuptake of bile (bile is high in cholesterol)

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22
Q

Where is ezetimibeglucuronidated?

A

In the intestine by UGT1A1, 1A3, 2B7

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23
Q

What are the side effects of ezetimibe?

A

Fatigue in ~2%

GI diarrhea in 2 - 4%

Increase transaminases in ~1%

Arthralgia in 3%

URTI symptoms in 3%

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24
Q

How many doses of ezetimibe are needed daily?

A

Due to 22 hour half life it only needs to be taken once daily

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25
How potent is ezetimibe at reducing cholesterol?
Not very, but when combined with statins it can have a huge effect.
26
How does ezetimibe affect triglycerides and HDL?
Minimal changes to TG and minimal increase to HDL
27
What was the CVD outcome of ezetimibe?
It improved the condition. It is great for sparing statins in those with muscle symptoms
28
What do PCSK9 receptors do?
Receptor present in liver and kidneys associated with hypercholesterolaemia. Loss of function mutations were associated with reduction in CVD risk (28.8% reduction in risk)
29
What is PCSK9 gene expression regulated by?
SREBP2 in response to cholesterol levels
30
What did monoclonal antibodies against PCSK9 do in phase 1 trials?
Reduced LDL-c by 50 - 70% Active in addition to statins (compound effect) No heterogeneity in studies Reduce Lp(a) (25%) Reduce TG (10-30%) Increase HDL (10%)
31
What is the function of PCSK9?
Recycling of LDL-Receptors. If PCSK9 loses function then receptors don't get recycled resulting in less LDL binding and breakdown
32
What are the side effects of PCSK9 inhibitors?
Nasopharyngitis Injection site reactions 5% GI 1 - 6% Hypertension 3% Neurocongnitive 1%
33
What is the problem with using PCSK9 inhibitors?
They have to be injected every 2 - 4 weeks and taken in addition to statins
34
What is evolocumab?
TGA approved cholesterol lowering drug. New drug used to treat familial hypercholesterolaemia or clinical ASCVD (atherosclerotic cardiovascular disease)
35
What are the TGA and PBS approved drugs to use for cholesterol?
Alirocumab Evolocumab
36
What did fourier test result in?
21-27% reduction in CVD events but did not reduce CV mortality or all cause mortality
37
What were the problems with using an ApoB antisense?
Increased hepatic fat 90% injections site reactions and 50% influenza symtoms
38
What does ApoB do?
Stop production of ApoB which prevents export of lipoproteins from the liver
39
What were the side effects of MTP inhibitor?
Increase in hepatic fat and transaminase levels due to decrease in formation and release of lipoproteins from the liver
40
What are the secondary causes of hypercholesterolaemia?
Lifestyle
41
What are the secondary causes of hypercholesterolaemia?
Lifestyle (Weight loss, alcohol, controlling diabetes)
42
What are fibrates?
PPARalpha activators They increase FFA beta oxidation They down-regulate ApoCIII Increase catabolism (B48 in chylomicrons and B100 in VLDL)
43
What is the efficacy of fibrates like?
increased HDL by 5 - 20% Reduced TG by 5 - 20% If there is severe TG then it increases LDL severely
44
What was the overall result of using fibrates?
Meta analyisis of 45000 people showed no CVD benefit and trend to nonCVD harm RR=1.10ns
45
What are remnant lipoproteins
Total cholesteral - HDL - LDL. if that's greater than 1.5mmol/L then same risk as someone with LDL greater than 5mmol/L
46
Who benefits most from fibrates?
people with dyslipidaemia (abnormal amounts of fat in blood)
47
What are n3 Polyunsaturated FAs?
They reduce fatty acid synthesis and are complex and multifactorial.
48
What are some examples of n3 Polyunsaturated FAs?
EPA and DHA
49
What do n3 Polyunsaturated FAs do?
They reduce triglycerides VLDL and non-HDL cholesterol while increasing LDL-c
50
What is the benefit of consuming more polyunsaturated FAs?
Consuming marine based PUFAs reduces CVD Lower triglycerides with a dose response. 9 - 26% change
51
What does Niacin do?
Reduces TG synthesis via decreased hepatic DGAT (diacylglycerol acyltransferase-2) Also reduces FFA flux from adipose tissue and enhances TRL clearnance
52
How effective is Niacin?
Lowers TG 5 - 40% Lowers LDL-c and Lp(a) Increases HDL However, no improvement was seen in cardiovascular disease outcome.
53
What are the side effects of Niacin?
flushing Itch GI Hyperglycaemia
54
What is GLP1?
Glucagon like peptide 1 Secreted in response to a meal. Increases insulin, decreases glucagon, slows gastric emptying, and reduces caloric intake
55
What are the side effects of GLP1?
GI cramps, nausea, vomiting, and weight loss.
56
How effective was GLP1 at reducing TGs?
Reduced postprandial TGs on diabetics and IGT Unknown effects on CVD it's undergoing trials as we speak Reduces HbA1c
57
What does DPP-4 do?
Prolong activity of GLP1 increasing insulin production decreasing glucagon slowing gastric emptying reducing calorie intake
58
How often are DPP-4 inhibitors taken?
once a day orally
59
What are the side effects?
Hypoglycaemia if combined with GLP1 Headaches Nasopharyngitis Nausea Vomiting Weight loss Heart failure
60
How effective are DPP-4 inhibitors?
They reduce TGs effectively by ~15% May reduce LDL-c slightly Reduce post prandial triglycerides Not trialed yet so unkown how effective they are on CVD Reduces HbA1c by 0.5 - 1%
61
What are the DPP-4 inhibitors called pharmacologically?
gliptins
62
What are thiazolidinediones?
PPARgamma agonists They act on adipose tissue, muscle and liver increasing glucose uptake and decreasing glucose production
63
What are side effects of thiazolidinediones?
weight gain Oedema Long bone fractures Bladder cancer
64
What is the most fundamental way to lipid therapy?
Mediterranean diet Exercise and smoking cessation
65
How can LDL-c be lowered?
Statins are first line therapy (More = better but SEs are problematic) Ezetimibe is the second line (some CVD outcome benefit and is a statin sparing agent) PCSK9 inhibition through monoclonal antibody therapy is important to reducing cholesterol Triglyceride reduction should be done after CVD risk is improved with statins and other stuff. Lifestyle should be fixed with alcohol reduction Fish oil due to the EPA and DPA content Fibrates reduce CVD morbidity in diabetic dyslipidaemia by 25% Diabetes control

IMED3001 (46 decks)

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