lipid lowering therapies Flashcards
What do lipoproteins do?
They carry fats around the bloodstream
What percentage of cholesterol is carried by LDL?
70%
What is Lp(a) concentration determined by and why is it important?
It is very atherogenic and it is purely determined by genetics
What are the good bad and ugly lipoproteins (not technical terminology by any means but helps understand better)?
Good: HDL
Bad: VLDL, IDL, LDL, Lp(a)
Ugly: IDL, chylomicron remnant, Lp(a)
What is characteristic of the exogenous lipoprotein transport pathway?
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.
Which body parts have Lipoprotein Lipase?
Muscles and adipose tissue
What is the endogenous lipoprotein pathway?
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.
What receptor do VLDL, IDL, and LDL use in the endogenous pathway?
Apo(B100)
How can cholesterol be lowered?
Lower saturated fats
How can triglycerides be lowered?
Low energy and weight loss
How do statins work?
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.
Where do lipophilic statins tend to go more often?
To the brain and muscles more than hydrophilic statins
What P450 can we find on Atorvastatin?
3A4 (important to know)
What P450 receptor is present on Rosuvastatin?
2C9 (limited)
What do statins do?
They can effectively reduce LDL-cholesterol
How do LDL -C levels correlate with CHD events?
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
What are the hepatic side effects of statins?
Mild increase in transaminase (0.5 - 3%)
What are the cognitive side effects of statins?
Memory lass (rare)
Others suggest may prevent dementia
What do statins do to diabetes risk?
9% increase and linked to HMG CoA reductase
What are statin side effects on muscle injury?
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
How does ezitimibe reduce cholesterol?
By decreasing the reuptake of bile (bile is high in cholesterol)
Where is ezetimibeglucuronidated?
In the intestine by UGT1A1, 1A3, 2B7
What are the side effects of ezetimibe?
Fatigue in ~2%
GI diarrhea in 2 - 4%
Increase transaminases in ~1%
Arthralgia in 3%
URTI symptoms in 3%
How many doses of ezetimibe are needed daily?
Due to 22 hour half life it only needs to be taken once daily
How potent is ezetimibe at reducing cholesterol?
Not very, but when combined with statins it can have a huge effect.
How does ezetimibe affect triglycerides and HDL?
Minimal changes to TG and minimal increase to HDL
What was the CVD outcome of ezetimibe?
It improved the condition.
It is great for sparing statins in those with muscle symptoms
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)
What is PCSK9 gene expression regulated by?
SREBP2 in response to cholesterol levels
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%)
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
What are the side effects of PCSK9 inhibitors?
Nasopharyngitis
Injection site reactions 5%
GI 1 - 6%
Hypertension 3%
Neurocongnitive 1%
What is the problem with using PCSK9 inhibitors?
They have to be injected every 2 - 4 weeks and taken in addition to statins
What is evolocumab?
TGA approved cholesterol lowering drug.
New drug used to treat familial hypercholesterolaemia or clinical ASCVD (atherosclerotic cardiovascular disease)
What are the TGA and PBS approved drugs to use for cholesterol?
Alirocumab
Evolocumab
What did fourier test result in?
21-27% reduction in CVD events but did not reduce CV mortality or all cause mortality
What were the problems with using an ApoB antisense?
Increased hepatic fat
90% injections site reactions
and 50% influenza symtoms
What does ApoB do?
Stop production of ApoB which prevents export of lipoproteins from the liver
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
What are the secondary causes of hypercholesterolaemia?
Lifestyle
What are the secondary causes of hypercholesterolaemia?
Lifestyle (Weight loss, alcohol, controlling diabetes)
What are fibrates?
PPARalpha activators
They increase FFA beta oxidation
They down-regulate ApoCIII
Increase catabolism (B48 in chylomicrons and B100 in VLDL)
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
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
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
Who benefits most from fibrates?
people with dyslipidaemia (abnormal amounts of fat in blood)
What are n3 Polyunsaturated FAs?
They reduce fatty acid synthesis and are complex and multifactorial.
What are some examples of n3 Polyunsaturated FAs?
EPA and DHA
What do n3 Polyunsaturated FAs do?
They reduce triglycerides
VLDL and non-HDL cholesterol while increasing LDL-c
What is the benefit of consuming more polyunsaturated FAs?
Consuming marine based PUFAs reduces CVD
Lower triglycerides with a dose response. 9 - 26% change
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
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.
What are the side effects of Niacin?
flushing
Itch
GI
Hyperglycaemia
What is GLP1?
Glucagon like peptide 1
Secreted in response to a meal. Increases insulin, decreases glucagon, slows gastric emptying, and reduces caloric intake
What are the side effects of GLP1?
GI cramps, nausea, vomiting, and weight loss.
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
What does DPP-4 do?
Prolong activity of GLP1
increasing insulin production
decreasing glucagon
slowing gastric emptying
reducing calorie intake
How often are DPP-4 inhibitors taken?
once a day orally
What are the side effects?
Hypoglycaemia if combined with GLP1
Headaches
Nasopharyngitis
Nausea
Vomiting
Weight loss
Heart failure
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%
What are the DPP-4 inhibitors called pharmacologically?
gliptins
What are thiazolidinediones?
PPARgamma agonists
They act on adipose tissue, muscle and liver increasing glucose uptake and decreasing glucose production
What are side effects of thiazolidinediones?
weight gain
Oedema
Long bone fractures
Bladder cancer
What is the most fundamental way to lipid therapy?
Mediterranean diet
Exercise
and smoking cessation
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
