Lipid-lowering medications: Fibrates

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Introduction0:00–0:15

Fibrates are a group of lipid-lowering medications, along with statins and niacin. These medications are very effective at lowering triglyceride levels in the blood, but are less effective at controlling cholesterol.

Pathophysiology0:15–3:36

Now, triglycerides make up most of your body fat, and they consist of a glycerol and 3 fatty acids. So when we eat a box of chili fries, the fatty acids and cholesterol are absorbed into the cells in the small intestine.
The fatty acids are then converted into triglycerides. However, triglycerides and cholesterol are 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 triglycerides 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 the liver and other tissues in the body.
Now in the blood vessels near these tissues, we have an enzyme called lipoprotein lipase, which can break down triglycerides into fatty acids.
Cells in the nearby tissue can then use these fatty acids to generate ATP. Adipose tissue can synthesize a lot of lipoprotein lipases, which means they have access to a lot of fatty acids.
Now, instead of using the fatty acids for energy, they pick them up, convert them back into triglycerides, and store them for later use.
Okay, so we can also synthesize fatty acids from glucose in the liver which are then converted into triglycerides. These triglycerides and some cholesterol 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 to carry the energy-rich triglycerides to the rest of the body. Now, lipoprotein lipases in the blood vessels will once again convert the triglycerides in the VLDLs into fatty acids, which can enter the cells; and the leftover VLDLs are called VLDL remnants.
This and the the remaining cholesterol are converted into 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 and 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 releases 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, triglycerides are atherogenic which means they can cause atherosclerosis, increasing the risk of cardiovascular complications like strokes and myocardial infarctions.
Extremely high triglyceride levels can also lead to acute pancreatitis. Okay, so if we want to lower triglyceride levels we can use a class of medications called fibrates.

Mechanism of Action3:36–5:00

Common medications in this class include gemfibrozil, bezafibrate, and fenofibrate. They all work by activating a intranuclear receptor called PPARα, or peroxisome proliferator-activated receptor alpha.
PPARα is a major regulator of lipid metabolism and when activated by fibrates, it’ll cause adipose cells to produce more lipoprotein lipase, which increases the conversion of the triglycerides in chylomicrons and VLDLs into fatty acids, thus lowering triglyceride levels.
Next, in the liver, fibrates increase the breakdown of triglycerides through beta oxidation so we make less VLDLs which also results in lower triglyceride levels.
Finally fibrates also increase the synthesis of HDL, which can provide a moderate decrease in cholesterol. Now unlike statins, which are the more commonly used lipid lowering agent, fibrates have little effect on LDLs, so they don’t lower cholesterol as much.
On the other hand, statins are not as effective in lowering triglyceride, so the two can be combined to tackle mixed dyslipidemia, where both triglyceride and cholesterol levels are elevated.

Side effects5:00–5:49

Okay for side effects, the most common ones include GI disturbances and rashes. A more serious side effect is that fibrates can damage the muscles and lead to rhabdomyolysis, or muscle break down.
Since statins can also cause this problem, when they are combined, the risk is increased. Next in the liver, fibrates decrease the activity of an enzyme called cholesterol 7 alpha-hydroxylase, which is needed to convert cholesterol into bile acid.
So we end up with a lot of cholesterol in the bile, and this promotes the formation of gallstones. Now another class of lipid lowering medications called bile acid resins also cause gallstone formation, so if used together with fibrates, the risk of developing gallstones is increased even more!
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharm facts! So let’s have a lady at a loom making fabrics, for fibrates.

Memory Palace5:49–7:15

Now the finished fabrics are placed on the top shelf inside a heavy metal box, which represents HDL. Since it’s on the top shelf, it means fibrates lead to a higher level of HDL.
Now, her supplies are on the bottom shelf and they are in a very light cardboard box for VLDL and a wooden box for LDL. Now notice the largest of the boxes is the cardboard box, while the smallest box is the wooden one.
So fibrates are most effective at lowering VLDL, and triglycerides have a moderate effect at increasing HDL, and very low effect on lowering LDL.
Okay for some of the important side effects, let’s use the lady’s husband. He’s a super muscular guy but his muscles are all red and swollen from carrying all the boxes, and this represents rhabdomyolysis.
He has the word “Statin” tattooed to his arm to help you remember statins can worsen this problem if used together with fibrates.
Next, let’s have him hold a giant gallstone, which is another side effect. On top of the gallstone is a raisin covered in green, slimy bile, since bile resin will increase the risk even more.
All right, as a quick recap, fibrates increase triglyceride clearance from the body and work by inducing lipoprotein lipase via activation of PPARα nuclear receptors.

Review7:15–7:42

While less commonly used, they are very effective at lowering triglyceride levels or are sometimes combined with statins to lower both triglyceride and cholesterol.
The main toxicity of fibrates includes myositis and rhabdomyolysis. But wait, there’s more: Here’s a mind map with all of the mnemonics.

Mind Map7:42–7:53

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.