Miscellaneous lipid-lowering medications
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AssessmentsMiscellaneous lipid-lowering medications
Miscellaneous lipid-lowering medications
Miscellaneous lipid-lowering medications exam links
Content Reviewers:Yifan Xiao, MD
Contributors:Tanner Marshall, MS, Sam Gillespie, BSc, Ursula Florjanczyk, MScBMC
Lipid-lowering medications work to decrease levels of cholesterol and triglycerides in the body.
Several medications fall outside the more commonly used classes like statins and fibrates, so in this video, we're going to discuss the bile acid resins, niacin or vitamin B3, ezetimibe, and the PCSK9 inhibitors.
Although it’s got a bad reputation, cholesterol is actually a critical component of our cells and is used to build the cell membrane.
It also has other uses like the synthesis of: steroid hormones, vitamin D, and bile.
Normally, we get our cholesterol from the food we eat, but it can also be synthesized by the liver.
So when we eat a box of chili fries, the fats and cholesterol are absorbed in the small intestine.
However, they’re not water soluble, so they can’t travel freely in the blood.
To fix this, our body makes shipping boxes called lipoproteins.
These containers consist of a shell made of phospholipids and protein tags that act as instructions for their destination.
So after absorption, the small intestinal cells package the fats and cholesterol into the largest but least dense lipoproteins, called chylomicrons.
These are released into the lymphatic system and then enter the bloodstream via the subclavian vein. Then they travel through the blood to reach adipose tissue and the liver.
Now, the liver can also synthesize intrinsic cholesterol through the mevalonate pathway, which happens in the smooth endoplasmic reticulum of liver cells.
It begins with 2 acetyl-CoA molecules getting joined together by the enzyme acetyl-CoA acyl-transferase. The result is a 4-carbon molecule called acetoacetyl-CoA.
Next, the enzyme HMG-CoA synthase combines acetoacetyl-CoA and acetyl-CoA to form a 6-carbon molecule called 3-hydroxy-3-methylglutaryl CoA, or HMG-CoA.
Then, an enzyme called HMG-CoA reductase reduces HMG-CoA into mevalonate. This step with HMG-CoA reductase is the rate-limiting step of cholesterol synthesis.
In other words, the rate of this reaction determines the overall rate of cholesterol synthesis, it’s like the slowest step of an assembly line in a factory.
Mevalonate is the precursor molecule that will eventually become cholesterol.
Okay, in the liver, cholesterol and a lot of triglycerides are packed into the next kind of lipoproteins called very-low-density lipoproteins or VLDL, which are smaller and more dense than chylomicrons.
This package is sent into the bloodstream and carry the energy-rich triglycerides to the rest of the body.
Now, after unloading their triglycerides, the VLDL and the remaining cholesterol become a new kind of lipoprotein, called a low-density lipoprotein, or LDL, which are even smaller and more dense than VLDL. These will travel around the bloodstream and deliver cholesterol to cells in the rest of the body.
The final lipoprotein is the HDL, or high-density lipoprotein, which are smaller but denser than LDLs. These are like the boxes you get when you try to return an item you bought online.
In this case, the liver produces HDL and released them into the blood, where they pick up excess cholesterol from the peripheral tissues and brings them back to the liver.
So in essence, it’s the opposite of LDL, which carries cholesterol from the liver to the peripheral tissues.
Now, the tissues in the body will take in the LDLs, as well as the cholesterol that’s contained in them.
So, if we have too much LDL, we get cholesterol build up in these tissues.
One of the most clinically relevant tissues is the endothelium that lines the blood vessels.
Increased cholesterol here will lead to the formation of fatty deposits called plaques, and these will increase the risk of cardiovascular complications like strokes, myocardial infarctions, and peripheral vascular disease.
Now, our miscellaneous lipid lowering agents act at several points during lipid metabolism.
The first group of medications are the bile acid resins like cholestyramine, colestipol, and colesevelam.
These are large, positivity charged molecules that bind to the negatively charged bile acid in the intestine.
Being stuck to the resin keeps bile acid from being reabsorbed, and they get excreted with the stool.
So, since we are depleting bile acid, the liver will compensate by increasing the production of bile salts, and this uses up a lot of cholesterol.
To get more cholesterol from the rest of the body, the hepatic cells increase the number of LDL receptors on their surface, which facilitates the uptake of cholesterol-rich LDLs, thus further lowering cholesterol levels in the blood.
However, the liver also increases the synthesis of HMG-CoA reductase, which synthesizes more cholesterol.
This means these medications are not as effective as the statins in decreasing LDL cholesterol, since statins increase the LDL receptors and inhibit HMG-CoA. So bile acid resins are usually used together with statins.
Next, the LDL receptors also very slightly increase the uptake of VLDL.
Although these drugs can also cause a very small increase in HDL, their main use is to treat high levels of LDL cholesterol.
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