Nearly one-third of Americans have high cholesterol putting them at risk for heart disease and stroke (two leading causes of death within the United States). So, if you are one of these Americans, then your primary care provider has probably recommended lifestyle changes (i.e., diet and exercise), and, if warranted, a statin drug may have been prescribed.
Unfortunately, for some individuals, these interventions aren’t enough, and their cholesterol levels remain too high. There are various reasons this may occur, such as unable to tolerate statins due to side effects or the drug treatment just isn’t enough to control their cholesterol.
In 2015, a new class of medication called PCSK9 inhibitors became available in the U.S. to help lower “bad” cholesterol. These agents lower cholesterol so well (up to 60% in some cases) that they are being touted as game-changing agents for the management of high cholesterol.
How Do PCSK9 Inhibitors Work?
When cholesterol is present in the blood, it clumps together and forms lipoproteins. The two most common lipoproteins are low-density lipoproteins (LDL) and high-density lipoproteins (HDL). They are commonly referred to as “bad” cholesterol and “good” cholesterol, respectively.
But how do you remember which type of cholesterol is which?
- “H” for Healthy HDL – is known as healthy/good cholesterol because it acts like a vacuum sucking up cholesterol that can build up on the sides of your arteries
- “L” for Lousy LDL – is known as lousy/bad cholesterol because too much of it will harden the arteries and lead to decreased oxygen-rich blood and increase the risk of blood clots.
PCSK9 inhibitors are a type of biologic drug called monoclonal antibodies that specifically target LDL (lousy) cholesterol.
These drugs block an enzyme in the liver (proprotein convertase subtilisin kexin 9) that inactivates receptors on the liver responsible for breaking down LDL cholesterol.
Therefore, by blocking PCSK9, there are more receptors available on the surface of the liver to reduce the amount of LDL cholesterol in the bloodstream.
What Did the Clinical Studies Show?
Repatha® (evolocumab) is administered every two weeks (140 mg) or once a month (420 mg). A study called FOURIER showed that evolocumab decreased the risk of heart failure death, heart attack, stroke, and hospitalization for chest pain.
Another study looked at the effect of Repatha and statin treatment for patients who need to decrease their LDL levels in the hospital.
The study showed that evolocumab lowered LDL to the target level in 96% of patients when it was added to statin medications.
Praluent® (alirocumab) is administered every two weeks (75-150 mg). A study called ODYSSEY OUTCOMES showed that alirocumab decreased the risk of patients having a heart attack, stroke, and death from heart disease. Moreover, a long-term study showed a 58% decrease in LDL by week 24 among those who took alirocumab.
A New PCSK9 Inhibitor Under Investigation
Inclisiran is a new investigational agent that is being studied for its cholesterol-lowering properties. This agent is a first-in-class small interfering RNA molecule drug that targets the production of PCSK9 in the liver.
Phase 3 trials (ORION-9, -10, -11) showed inclisiran decreased LDL levels by 51% compared to placebo (no medication). Another study, called ORION-4, is currently underway evaluating the long-term effects of inclisiran on death, heart attack, and strokes over five years.
If approved, inclisiran would be administered by injection twice yearly. Common side effects observed in clinical trials included high blood pressure, the common cold, and diabetes.
Who Should Take a PCSK9 Inhibitor?
A PCSK9 inhibitor may be recommended by a healthcare provider when:
- An individual has familial hypercholesterolemia (a genetic cause of high cholesterol)
- An individual cannot tolerate statins due to side effects (e.g., muscle or liver damage)
- An individual’s cholesterol (despite taking conventional cholesterol-lowering treatment) remains too high increasing their risk of heart attack or stroke
PCSK9 Inhibitor Side Effects
The majority of side effects experienced by patients are mild and include back pain and symptoms of the cold or flu.
Since these agents are injectables, individuals may also experience injection-site reactions (e.g., redness, bruising, injection-site pain).
If you think you are experiencing a side-effect, you can reach out to your pharmacist or primary care provider for more information.
Serious allergic reactions have also been observed in some patients.
Any individual with signs or symptoms of an allergy, such as a severe rash, swollen face, or difficulty breathing, should seek out emergency services right away.
References, Studies and Sources:
- Centers for Disease Control and Prevention. Cholesterol. CDC https://www.cdc.gov/cholesterol/index.htm. Accessed 12 July 2020.
- Centers for Disease Control and Prevention. Familial Hypercholesterolemia. CDC. https://www.cdc.gov/genomics/disease/fh/FH.htm. Accessed 12 July 2020.
- Novartis. Novartis new analysis further shows durable and potent LDL-C reduction with inclisiran, an investigational first-in-class siRNA cholesterol-lowering treatment. Published 28 March 2020. https://www.novartis.com/news/media-releases/novartis-new-analysis-further-shows-durable-and-potent-ldl-c-reduction-inclisiran-investigational-first-class-sirna-cholesterol-lowering-treatment. Accessed 12 July 2020.
- Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis US. July 2015.
- Repatha [package insert]. Thousand Oaks, CA: Amgen; 2015.
- WebMD. Side Effects of Cholesterol Lowering Statin Drugs. https://www.webmd.com/cholesterol-management/side-effects-of-statin-drugs. Accessed 12 July 2020.
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