How Cholesterol Lowering Medications Work

Updated: Mar 15

There are two cholesterol lowing medications on the market. They are the statins, of which there are many brands (Zocor, Crestor, Lipitor), and then there are the newer PCSK9 inhibitors (Repatha). Both are effective at lowering LDL on a blood panel (if that is what you want), but how they do it can have some consequences. To understand the consequences, we must look at how each of these drugs work.

Let’s tackle the infamous statins drugs first. Statins work by directly preventing the production of cholesterol. To understand how, and to understand the consequences, we need to first become familiar with the basic steps through which the body makes cholesterol. The process has many steps, it starts with the synthesis of Acetyl-CoA from either glucose (glycolysis) or fatty acids (beta-oxidation). From there the basic steps to making cholesterol goes like this (though this is simplified):

Acetyl-CoA --> HMG-CoA --> Mevalonate --> Mevalonyl-PP --> Isopentenyl-PP --> Geranyl-PP --> Farnesyl-PP --> Squalene --> Cholesterol

Stains are called HMG-CoA reductase inhibitors because they inhibit the enzyme (HMG-CoA reductase) that converts HMG-CoA to Mevalonate. Since this blocks the production of Mevalonate we don’t get to make cholesterol in the end. Just as important though, is that we don’t make any of the intermediates between Mevalonate and cholesterol. There are a few intermediates that are particularly important.

The first is Isopentyl-PP. When the process to making cholesterol gets to this point some of this molecule that is available does indeed go on to make cholesterol, but some of it is used for other purposes. One thing it is used for is the making of Selenoproteins. The most famous of these is glutathione peroxidase, the main antioxidant made in the body. Sufficient levels of this antioxidant in the body are essential for protecting the tissues in the body from getting damaged, including our DNA. If we block HMG-CoA from becoming Mevolonate we will never get Isopentyl-PP and therefore end up with less protective antioxidants. (1) This is a recipe for what is called oxidative stress.

Isopentyl-PP is also important for the conversion of vitamin K1 to K2. K2 is known to aide in the prevention and reversal of calcification in the arteries. (2) It does this through activation of the matrix GLA protein. Again, if the previous step of HMG-CoA to Mevalonate is stopped then we never get Isopentyl-PP and therefore cannot depend on the conversion of K1 to K2 to help prevent atherosclerosis. Despite statins being touted as something that will prevent atherosclerosis, this is a mechanism by which it will deprive the body of something it needs to prevent atherosclerosis and therefore cause it.

Moving down the line of cholesterol synthesis, we will next take a look at Farnesyl-PP. This intermediate is only two steps away from being cholesterol, but it is also used to make CoQ10. This is a popular supplement used for heart health. Its most important job is the health and productivity of making ATP in our mitochondria. The heart is one of the most mitochondrial dense tissues in the body which is why CoQ10 is supplemented for heart health. However, if the intermediate Farnesyl-PP isn’t made because of statins blocking the production of cholesterol then we don’t get CoQ10 (3) and we get less than optimal ATP production. This could be why statins have been shown to cause fatigue and cardiomyopathy. (4) Also, since muscles are very metabolically active tissues, it could also explain the muscle pain side effect of statins. (5)

Farnesyl-PP is also used to make another molecule named dolichol. Dolichol plays a key role in the function of insulin receptors throughout the body. If we do not have enough Farnesyl-PP to make dolichol we can end up with less than optimal function of our insulin receptors which can cause what would look like insulin resistance. Knowing this, it is no surprise that it has been shown that the use of stains causes diabetes. (6) I wrote about the personal benefits I saw from haivng higher LDL and plenty of dolichol in my post on the many benefits of LDL.

Lastly, the mere fact that a statin is preventing the synthesis of cholesterol can be problematic. I discussed all the beneficial effects of having lots of LDL transporting cholesterol around the body in this blog post. To summarize, some of the benefits of cholesterol are defense against infection, cell repair, reducing inflammation, synthesis of hormones and Vitamin D, transport of fat-soluble vitamins, energy delivery, muscle function, neurotransmitter signaling, and prevention of vascular calcification.

With all those benefits I would not want to inhibit the creation of cholesterol in my body. Not only that, but I would not want to interfere with my bodies’ ability to use the cholesterol either, this is exactly what the other LDL lowering medication called PCSK9 inhibitors do.

PCSK9 is the molecule that blocks or removes LDL receptors on cells so that LDL is not taken out of the bloodstream and into the liver. PCSK9 is stimulated to do this and leave LDL in the blood if there is a lot of inflammation or an infection that the LDL can help deal with. What a PCSK9 inhibitor does is get rid of PCSK9 through an antibody mechanism. This then leaves all the LDL receptors open to take LDL into the cells and out of the blood stream. It definitely has the effect of lowering LDL on a blood lipid panel, but it then leaves you at risk for all the problems of not having LDL in the blood and without the benefits that LDL provides. PCSK9 inhibitors are new drugs, but early studies are showing problems already. (7)

As I mention in my post on the benefits of LDL, people with abetalipoproteinemia (genetically low LDL) have medical issues and do not live as long. (8) And before you say that yes LDL is good but becomes a problem when it is too high, we need to look at people with familial hypercholesterolemia (genetically high LDL). These people don’t die any sooner those with normal LDL and have even been shown to have benefit in times of high infection rates throughout history. (9)

There you have it. That is how the LDL lowering drugs work and the effects they have. I do not think LDL is bad and therefore does not need to be lowered. Whether or not you take one of these drugs is up to you and your doctor. I hope I have provided information that you can take to your doctor to discuss with them so the best decision for your health can be made.

Stay healthy out there!

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