Page created on January 31, 2019. Last updated on January 7, 2022 at 22:03
Lipoproteins carry lipids in the blood, mostly triacylglycerols (also called triglycerides) and cholesterol. We have multiple types, VLDL, LDL, and HDL, where VLDL contains the most lipid and HDL contains the least.
The liver uses VLDL and LDL to transport lipids to the extrahepatic tissues that need energy. HDL carries cholesterol from the extrahepatic tissues back to the liver. Tissues, including the liver, take up LDL using receptor-mediated endocytosis, which means that LDL binds to the LDL receptor which causes the LDL to be endocytosed.
Lipoprotein lipase (LPL) is an enzyme that breaks down triacylglycerols inside lipoproteins into free fatty acids and glycerol. These can then be taken up and used by adipocytes and muscle cells.
More about these pathways can be refreshed from biochemistry.
The enzyme HMG-CoA reductase or simply HMGCR is the rate-limiting step of the mevalonate pathway, which produces cholesterol. If we inhibit this enzyme can we effectively decrease the synthesis of cholesterol.
The transcription of both HMGCR and LDL receptor is controlled by a transcription factor called SREBP. When the level of cholesterol in the liver is low will SREBP be activated, which increases transcription of HMGCR and LDL receptor, both of which aim to increase the levels of cholesterol in the liver back to normal. With more HMGCR molecules will the liver produce more cholesterol, and with more LDL receptors will the liver take up more cholesterol from the plasma.
We can differentiate two types of hyperlipidaemias. In hypercholesterolaemia is the level of lipoproteins abnormally high, and in hypertriglyceridaemia is the level of serum triacylglycerols high.
Hypercholesterolaemia occurs when the total serum cholesterol is more than 240 mg/dL, however the desirable level is less than 200 mg/dL. It’s almost always due to high levels of LDL, the level of which should be below 160 mg/dL but ideally below 100 mg/dL. It’s very closely linked to atherosclerosis and therefore also coronary artery disease.
It can occur secondarily due to diseases like hypothyroidism, primary biliary cirrhosis, or due to drugs liv HIV-proteinase inhibitors. However, most cases are primary, where there are genetic factors involved.
99% of cases of primary hypercholesterolaemia are not due to one single gene but is rather polygenic. These cases don’t have a clear pattern of inheritance.
1% of cases however are due to problems of one or both of the genes for the LDL receptor. This condition is called familial hypercholesterolaemia. If one is heterozygote for a mutant LDL receptor gene will that person only have 50% of the amount of LDL receptor that a normal person has, which drastically increases the serum cholesterol level. This predisposes to coronary artery disease in early childhood.
The homozygotes have it even worse. They have absolutely no LDL receptors so it’s almost impossible to remove LDL from the serum. This can give coronary artery disease as early as 5 years of age!
Hypertriglyceridaemia occurs when the serum triglyceride level is above 200 mg/dL, but the level should ideally be below 150 mg/dL. This is mostly due to increased level of VLDL or chylomicrons. It’s closely linked to acute pancreatitis, but also to coronary artery disease.
Like hypercholesterolaemia, hypertriglyceridaemia is most commonly primary, however it can be secondary due to diabetes, metabolic syndrome, alcoholism, oral contraceptives or HIV-protease inhibitors.
Most cases of primary hypertriglyceridaemia are polygenic, however monogenic causes exist, like familial lipoprotein lipase deficiency or type III hyperlipoproteinaemia, both of which increase the levels of VLDL and chylomicrons.
Treatment of hyperlipidaemias doesn’t involve immediately giving drugs. The treatment protocol is like this:
- Physical training – increases LDL receptor expression
- Dietary restriction – less cholesterol, fat and saturated fat intake
- Elimination of other risk factors that aggravate atherosclerosis, like hypertension, obesity, smoking
- Treatment of underlying disease – if the hyperlipidaemia is secondary
- Treatment with lipid-lowering drugs
Many risk factors predispose to atherosclerosis, like:
- Age >45
- Family history of coronary artery disease
- Low HDL levels
When treating a patient for hypercholesterolaemia must we take these risk factors, present diseases and the current LDL level into consideration. The more risk factors the patient has and the worse the condition of the patient, the more aggressive should the treatment be, and the lower the target serum cholesterol level should be. This makes sense.
The first-line treatment for reaching LDL targets are the statins. The second-line is statin + ezetimibe.
We divide the lipid-lowering drugs into two classes – whether they primarily decrease cholesterol or triacylglycerols.
- High intensity statins
- Moderate intensity statins
The first line treatment for hypercholesterinaemia and therefore most important drugs here are the statins.
The higher the dose of statins, the greater the decrease in LDL cholesterol levels. At the lowest recommended dose they reduce the level by 30 – 40%.
Atorvastatin and rosuvastatin, are the most frequently used ones, because they are more efficacious, which is why they’re “high intensity statins”. Atorvastatin 10 – 20 mg or rosuvastatin 5 – 10 mg causes 30 – 40% reduction in LDL, while atorvastatin 40 – 80 mg or rosuvastatin 20 – 40 mg causes 40 – 60% reduction, and giving either of these in these high doses is called “high intensity statin therapy”, which is the only therapy which can cause plaque regression, i.e. reversal of atherosclerosis. This is proven to be very beneficial and so in most cases of hypercholesterolaemia high intensity statin therapy is recommended.
Mechanism of action
These drugs inhibit HMGCR very effectively. When they do this will the level of cholesterol in the liver decrease, which activates SREBP. SREBP will then increase transcription of HMGCR (which doesn’t matter, as they’re inhibited by the statins anyway) and LDL receptor. It is this increased expression of LDL receptor that mediates the serum cholesterol-lowering effect of the statins, as the liver will endocytose more LDL from the serum.
Statins also have other beneficial effects:
- They promote vasodilation in atherosclerosis
- They stabilize atherosclerotic plaques
- They increase bone mineral density in osteoporosis
- They have other anti-inflammatory, neuroprotective and anticarcinogenic effects
They have low oral bioavailability, because the transport protein OATP1B1 transports the drug into the liver during the first pass effect. This is actually desirable, as the drug mainly works on the liver anyway. Also, statins are toxic to muscles, and this first pass effect helps keep the statins away from the systemic circulation and therefore away from the muscles. Genetic mutations in OATP1B1 predisposes individuals to muscle damage in response to statins.
Most statins are eliminated by biotransformation, while pravastatin and rosuvastatin are eliminated by urinary and biliary excretion, respectively.
Lovastatin, simvastatin and atorvastatin are eliminated via biotransformation by CYP3A4, meaning that they interact with drugs that are CYP3A4 inhibitors like erythromycin and HIV-protease inhibitors.
Lovastatin, simvastatin, pravastatin and fluvastatin have short (2-3 hours) half-life, while atorvastatin and rosuvastatin have long half-life.
Rosuvastatin can not be given in chronic kidney disease when GFR is < 30, but atorvastatin has no such contraindications. All statins are contraindicated in cases of significant liver enzyme elevation or active hepatitis.
Statins may cause both liver injury and muscle injury, however in most cases is this damage asymptomatic and only visible on blood tests. One of the most common side effects is muscle pain, but overt myopathy or rhabdomyolysis occurs in a small percentage of patients.
The risk for statin-induced injury increases substantially when a statin metabolised by CYP3A4 is taken together with a CYP3A4 inhibitor like verapamil, HIV protease inhibitors, and clarithromycin.
Cholesterol absorption inhibitors
The latter isn’t much used and therefore not important. Ezetimibe block the intestinal absorption of cholesterol from food. This indirectly decreases the cholesterol level in the liver, which causes it to upregulate LDL receptor and HMGCR as well. These drugs are therefore also best taken together with statins, and are commonly added to statins if the LDL target is not reached.
PCSK9-inhibitory monoclonal antibodies
These include alirocumab and evolucumab bind to a protein called PCSK9. This protein usually causes degradation of LDL receptor, but when the antibodies bind to it will this degradation not occur.
These drugs are well tolerated and very effective, as they can reduce LDL cholesterol levels by 50-70%. They’re very recent drugs (2015) so long-term tolerability hasn’t been determined yet. They are mostly used together with statins in people with familial hypercholesterolaemia or in people who didn’t reach the target serum cholesterol level by using statins alone.
Bile acid-binding anionic resins
These are very large molecules with a molecular weight of around 1 million daltons. These drugs are taken orally as a suspension or a tablet. When inside the intestine will they bind strongly to bile acids, which prevents them from being reabsorbed into the circulation, and instead causes them to be excreted with the feces.
Bile acids are synthesized from cholesterol in the liver, so when we decrease the reabsorption of bile acids into the systemic circulation must the liver convert more cholesterol into bile acids. This decreases the serum level of cholesterol.
When the bile acid reabsorption is decreased will the cholesterol level in the liver be decreased as well. This activates SREBP, which increases expression of HMGCR and LDL receptor. Increased expression of LDL receptor is what decreases the serum levels of LDL, however the increased levels of HMGCR means that the liver produces more cholesterol. These drugs therefore aren’t used alone but rather together with statins, as the statins will block the extra HMGCR molecules.
The suspension tastes horribly apparently, which keeps patient compliance low for the suspension preparation. Colesevelam can be given as a tablet and is more potent, so less drug needs to be given and less bad taste needs to be tasted. It also causes less constipation than the other resins.
If you know what resin is is it easy to understand why patient compliance is low.
Fibrates like fenofibrate and gemfibrozil are a class of drugs that induce the expression of lipoprotein lipase. They do this by binding to an intracellular receptor called PPARα, which increases the expression of LPL and apolipoproteins that are components of HDL. These drugs therefore increase HDL levels as well, which is beneficial in coronary artery disease.
Serum triglyceride level is decreased by 40-55%, although this effect takes weeks to develop. HDL levels are elevated by around 10%.
Fibrates are also taken up into the liver by OATP1B1 just like the statins. This means that if fibrates are given together with statins is the risk for statin-induced myopathy increased. Also, gemfibrozil competes with statins for the enzyme UGT1A1 as well, making them an even worse combination. Fenofibrate isn’t metabolized by UGT1A1, so if a statin should be given with a fibrate should fenofibrate be used.
Fibrates are completely absorbed from GI and have extensive plasma protein binding.
Fibrates increase the risk of cholesterol bile stones because they increase the biliary cholesterol excretion. They may also cause myopathy.
Nicotinic acid, also known as niacin or vitamin B3 can also reduce triacylglycerol levels, but only in a very large dose. The recommended daily intake is 20 mg, however the triacylglycerol-lowering dose is 2-5 g.
Nicotinic acid binds to Gi-coupled receptors on adipose tissue, which inhibits the activity of hormone-sensitive lipase. This decreases the release of free fatty acids into the serum from adipose tissue, meaning that the liver has fewer fatty acids to produce VLDL with.
Nicotinic acid is very efficacious, as it can decrease triacylglycerol levels with up to 80%, and they act within days, in contrast to fibrates. It’s mostly used when triacylglycerol levels must be decreased immediately, like when the level is so high that acute pancreatitis is imminent. It’s not used in other cases as it has unwanted effects like skin vasodilation, itching, GI disturbance, hyperglycaemia, hyperuricaemia and liver injury.
27. Drugs that increase regional blood flow. Drug treatment of obesity
30. Anticoagulants, antiplatelet drugs