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  • Writer's pictureNick Allen

The next generation of cholesterol-lowering drugs

The role cholesterol plays in our health is complicated. It’s simply incorrect to view cholesterol as a harmful molecule — we couldn’t survive without it. In fact, it’s so essential that our bodies have designed a system to constantly synthesize cholesterol. The term cholesterol often carries a negative connotation, however, because of the well-studied correlation between high cholesterol and heart disease. Specifically, cholesterol in low-density lipoprotein particles (LDL-C) has been associated with coronary heart disease risk.


The role of dietary cholesterol, on the other hand, is still under much debate. It appears that the cholesterol we synthesize (and how this cholesterol is packaged) is more relevant than the cholesterol we eat. This is not to say that diet is unimportant. Diet, exercise, genetics, and much more can impact our blood levels of LDL-C.


Regardless of how your LDL-C becomes elevated, it’s important that you work with your doctor to keep it under control. Statins, such as atorvastatin (Lipitor) and rosuvastatin (Crestor), are currently the gold standard when it comes to cholesterol-lowering medication. They are extremely well-studied, but aren’t free of side effects. This is because these drugs inhibit an enzyme, HMG CoA reductase, that has a plethora of downstream effects. The primary consequence is inhibition of cholesterol synthesis, which results in the lowering of LDL-C.


A new class of drugs, PCSK9 inhibitors, share this common goal with statins. However, they use a different, more direct mechanism to lower LDL-C. As seen in Figure 1, LDL receptors take LDL particles out of the blood when concentrations are high. PCSK9 is a molecule that normally binds to these LDL receptors and leads them to destruction. The result is that LDL particles stay in the blood, and levels may be elevated to the point of increased disease risk.


Figure 1: (a) The normal function of the PCSK9 protein and (b) the impact of PCSK9 inhibitors on this process (image courtesy of Zhang et al., 2018).


PCSK9 inhibitors are antibodies that block this process from happening, meaning that the LDL receptors are left in place and can carry out their function, removing LDL particles from the blood. The result is a lowering of the LDL-C, and a corresponding lowered risk of heart disease.


The hope for this new class of drugs is that they will be more effective and come with less side effects. A 2014 study of evolocumab, a PCSK9 inhibitor, showed strong reductions in LDL-C when used alone and in combination with a statin.


There are still plenty of barriers impeding the use of these drugs, however. Antibody treatments require intravenous administration, whereas statins come in pill form. They are also far more costly at the current time. The first PCSK9 inhibitors to hit the market initially cost over $1000 per month, but that price has since gone down to approximately $500 per month. It remains an unreasonable cost for the average American, especially when statins are available as a cheaper, more accessible alternative.


Nevertheless, PCSK9 inhibitors offer a great deal of promise for mitigating the risk of heart disease. In the future, I would love to see these drugs used as early, preventive treatment for patients just beginning to see elevation in their LDL-C measurements. While it’s not the current practice, I think that being more aggressive with our approach early on will pay dividends in the form of reduced cardiac events later in life.


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