29. Drugs used to treat hyperlipoproteinemias

Biochemistry recap

Lipoproteins

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.

Cholesterol synthesis

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.

Hyperlipidaemias

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 and dyslipidaemia

Hypercholesterolaemia occurs when the total serum cholesterol is elevated. However, it’s often accompanied by a decrease in HDL. For this reason, the term dyslipiaemia is more appropriate.

Dyslipidaemia is very closely linked to atherosclerosis and therefore also cardiovascular disease. Most cases of dyslipidaemia are primary, where there are genetic factors involved. Rarely, dyslipidaemia is due to genetic disorders of lipoprotein metabolism. These are characterised by early onset and severe dyslipidaemia. This can give coronary artery disease as early as 5 years of age!

The first-line treatment of dyslipidaemia is non-pharmacological, including lifestyle changes. The first-line pharmacological treatment for reaching LDL targets are the statins. The second-line is addition of ezetimibe.

Hypertriglyceridaemia

Hypertriglyceridaemia occurs when the serum triglyceride level is elevated. It can cause acute pancreatitis and atherosclerosis.

Statins

Compounds

• High intensity statins
  • Atorvastatin (Lipitor®)
  • Rosuvastatin (Crestor®)
• Moderate intensity statins
  • Simvastatin
  • Fluvastatin
  • Pravastatin
  • Lovastatin

The first line treatment for dyslipidaemia, 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

Pharmacokinetics

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 some are eliminated by urinary or biliary excretion.

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.

Contraindications

Rosuvastatin can not be given in severe kidney failure, but atorvastatin has no such contraindications. All statins are contraindicated in cases of significant liver disease.

Side effects

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

Compounds

• Ezetimibe (Ezetrol®)
• (β-sitosterol)

The latter isn’t much used and therefore not important, but ezetimibe is widely used in combination with statins to treat dyslipidaemia.

Mechanism of action

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

Compounds

• Alirocumab
• Evolucumab

These drugs are well tolerated and very effective in dyslipidaemia, as they can reduce LDL cholesterol levels by 50-70%. They’re 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 and ezetimibe.

Mechanism of action

These drugs are monoclonal antibodies which 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.

Bile acid-binding anionic resins

Compounds

• Cholestyramine
• Cholestipol
• Colesevelam

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. These are not widely used.

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 the taste is bad and the patient compliance is low.

Mechanism of action

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.

Triglyceride-lowering drugs

Fibrates

• Fenofibrate
• Gemfibrozil

Fibrates 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.

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.

Nicotinic acid

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 flushing and itching, diarrhoea, hyperglycaemia, hyperuricaemia and liver injury.