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JAMA Patient Page
December 1, 2015

PCSK9 Inhibitors for Treating High Cholesterol

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Copyright 2015 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA. 2015;314(21):2320. doi:10.1001/jama.2015.13748

PCSK9 inhibitors are a new type of cholesterol-lowering medication available in the United States.

Cholesterol and Cardiovascular Disease

Several types of cholesterol occur in the bloodstream, the most important of which are low-density lipoprotein (“bad”) cholesterol (LDL-C) and high-density lipoprotein (“good”) cholesterol (HDL-C). Having high cholesterol generally refers to having high LDL-C levels. Having high LDL-C increases the risk of having plaque buildup inside blood vessels, a condition called atherosclerosis. When atherosclerosis occurs in the blood vessels of the heart or brain, it can lead to heart attacks and strokes, 2 forms of cardiovascular disease. Cardiovascular disease is currently the leading cause of death in the United States.

Lowering cholesterol with both lifestyle changes and medications helps lower the risk of developing and dying of cardiovascular disease. In some people, a healthy diet and regular exercise are enough; others require medications. The most common drugs used to lower cholesterol are statins, but in some people with high cholesterol, statins do not lower cholesterol levels enough. Others cannot take statins because of side effects such as muscle pain or liver problems.

PCSK9 Inhibitors: A New Treatment

PCSK9 inhibitors are monoclonal antibodies, proteins designed and created in a laboratory to recognize and attach to another protein. PCSK9 inhibitors target a protein called PCSK9 that raises LDL-C levels. When a PCSK9 inhibitor attaches to a PCSK9 protein, it stops the PCSK9 protein from working, which leads to lower LDL-C.

Clinical trials have shown that PCSK9 inhibitors are powerful in reducing LDL-C levels. Three studies published in April 2015 showed that in patients taking standard statin cholesterol-lowering treatment, adding PCSK9 inhibitors further reduced LDL-C by about 60%. There are 2 PCSK9 inhibitors currently approved in the United States by the US Food and Drug Administration: alirocumab and evolocumab. They are injected under the skin every 2 to 4 weeks and are not available as an oral pill. They are significantly more expensive than other cholesterol medications.

There are very limited uses for these new drugs. PCSK9 inhibitors can be used together with statins in people with cardiovascular disease and a very high risk of stroke or heart attack who do not reach their goal LDL-C levels with statins alone. Or they can be used instead of statins in people who have major side effects from statins. They can also be used in people with very high LDL-C levels due to a genetic condition called familial hypercholesterolemia.

Future Directions

Although lowering LDL-C levels is good, an important question is whether PCSK9 inhibitors improve cardiovascular disease outcomes; that is, if they lower the rates of heart attacks and strokes and prevent the development of heart failure. So far, there is no clinical evidence that this is the case. Trials focusing specifically on long-term cardiovascular outcomes and safety are under way, and the results of these trials in the next several years will be very important in determining whether PCSK9 inhibitors become a more common part of the regimen for treating high cholesterol.

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Sources: Evolocumab [From the Medical Letter]. JAMA. doi:10.1001/jama.2015.14772.

Sullivan D, Olsson AG, Scott R, et al. JAMA. 2012;308(23):2497-2506.

Shrank WH, Barlow JF, Brennan TA. JAMA. 2015;314(14):1443-1444.

Stein EA, Raal FJ. Curr Cardiol Rep. 2015;17(11):104.

Topic: Cardiovascular Disease