There are two PCSK9 inhibitors available in the U.S.: alirocumab and evolocumab.

FDA has approved alirocumab for adult patients:

• To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.
• As an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce LDL-cholesterol 

FDA has approved evolocumab for adult patients:

• To reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.
• As an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce LDL-cholesterol
• As an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia who require additional lowering of LDL-C.[1]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) recently has emerged as an important regulator of cholesterol metabolism. Increased activity is associated with higher LDL-cholesterol levels, and certain gain of function mutations cause autosomal dominant familial hypercholesterolemia with very high cholesterol levels, premature atherosclerotic vascular disease, and the development of tendon xanthomas. Those with reduced PCSK9 activity, whether due to genetic polymorphism or administration of monoclonal antibodies to PCSK9, have lower cholesterol levels and a reduced risk of cardiovascular disease. 

Normal cholesterol metabolism

LDL-cholesterol is normally cleared from the circulation as apoprotein B100 on the surface of LDL binds to LDL receptors on hepatic and extrahepatic tissues. LDL bound to its receptors undergoes a process of endocytosis. The endocytic vesicle fuses with lysosomes, increasing the intracellular concentration of free cholesterol. As the intracellular concentration of cholesterol increases, three events occur.

1. A decrease in the activity of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis
2. The activation of ACAT, an enzyme that increases the storage of cholesterol as a cholesterol ester
3. The reduced expression of LDL receptors on the cell surface

In this highly integrated system, as the cell takes up more cholesterol by this normal LDL-receptor pathway, de novo production of cholesterol decreases, and less is taken up by the LDL receptors. When LDL levels are particularly high or if they undergo modification, such as glycation or oxidation, they are more apt to be taken up by the scavenger pathway on endothelial cells, leading to the development of atherosclerotic plaques and vascular disease.

An important concept to recognize is that LDL receptors continually recycle back to the cell surface where they can bind and clear more LDL-cholesterol. PCSK9, a product of hepatocytes, is secreted into the plasma where it binds to the LDL receptor resulting in lysosomal degradation of the receptor. Thus, PCSK9 reduces the expression of LDL receptors on the cell membrane, thereby decreasing the clearance of LDL-cholesterol.

Statins decrease HMG-CoA reductase activity, reducing cholesterol synthesis. Reduced intracellular cholesterol leads to increased recycling and the expression of LDL receptors on the cell surface. This, in turn, allows for increased clearance of LDL-cholesterol by this non-atherogenic receptor-mediated pathway, leaving less LDL to be taken up by the scavenger pathway. However, statins also increase the activity of PCSK9. While statins are effective in reducing cholesterol levels, their efficacy diminishes with this increase in PCSK9 activity.

PCSK9

Familial hypercholesterolemia is a syndrome characterized by extremely high levels of total and LDL-cholesterol, premature vascular disease, and tendon xanthomas. In the vast majority of cases, it is due to a genetic mutation of the LDL receptor, rarely a mutation of the apoprotein B100 gene. In 2003, researchers found a family in France that had the familial hypercholesterolemia phenotype without an identifiable mutation of the LDL receptor or apoprotein B100. They were discovered to have a gain of function mutation of a serine protease, proprotein convertase subtilisin/kexin type 9 (PCSK9). Transgenic mice overexpressing PCSK9 have reduced LDL-R function and elevated LDL-cholesterol while PCSK9 knockout mice have increased LDL-R activity and low LDL-cholesterol levels. A longitudinal epidemiologic study found subjects with loss of function mutations in PCSK9 had a modest reduction in LDL-cholesterol but a more significant decrease in coronary heart disease.

Understanding these basic principles of cholesterol metabolism led to the hypothesis that measures to reduce PCSK9 activity would lower LDL-cholesterol levels and possibly reduce the risk of cardiovascular disease. At present, there are two pharmaceutical products available in the United States that reduce PCSK9 activity: alirocumab and evolocumab. Both are fully-humanized monoclonal antibodies that are injected subcutaneously at intervals of every 2 to 4 weeks and are highly potent in reducing total and LDL-cholesterol. Whether used as monotherapy or in combination with a statin, they typically lower LDL-cholesterol levels by 50% to 60%. The effect sustains as long as treatment continues.[2][3]

 Alirocumab 

• Supplied in 75 mg or 150 mg single-dose prefilled pen or syringe.
• The recommended starting dose is 75 mg once every two weeks administered subcutaneously.
• An alternative starting dose is 300 mg once every four weeks.
• If the LDL-C response is inadequate, the dosage may be adjusted to the maximum dosage of 150 mg administered every two weeks.

 Evolocumab 

• Supplied as 140 mg/mL single-use prefilled syringe or autoinjector or 420 mg/3.5 mL solution in a single-use on-body infusor with a prefilled cartridge.
• 140 mg every two weeks or 420 mg once monthly in the abdomen, thigh, or upper arm.
• 420 mg dose can be administered over 9 minutes by using the single-use infusor or by giving three 140 mg injections consecutively within 30 minutes.

No dose adjustment is necessary for patients with mild or moderately impaired hepatic or renal function. No data are available in patients with severe hepatic or renal impairment.

 Efficacy[2]

• Decrease LDL-cholesterol 45 to 70%
• Decrease apoprotein B 40 to 50%
• Decrease lipoprotein (a) 30 to 35%
• Decrease triglyceride 8 to 10%
• Increase HDL-cholesterol 8 to 10%
• Increase apoprotein A1 4 to 5%

 Outcomes data

Both short and long-term studies have shown a significant reduction in cardiovascular events.[4]

• Intravascular ultrasound evidence of plaque regression in patients on PCSK9 inhibitors (GLAGOV study).[5]
  • Evolocumab versus placebo x 76 weeks.
  • Decreased plaque volume and plaque regression in a greater percentage of treated subjects compared to placebo.
• FOURIER: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk.[6]
  • 27,564 subjects ages greater than or equal to 40 to less than or equal to 85 with clinically evident cardiovascular disease at high risk for a recurrent event with LDL-C greater than or equal to70 mg/dL or non-HDL-C greater than or equal to 100 mg/dL and triglycerides less than or equal to 400 mg/dL
  • Fifteen percent reduction in the primary endpoint, composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, hazard ratio, 0.85; 95% CI, 0.79 to 0.92
  • Twenty percent reduction in the secondary endpoint of cardiovascular death, MI, or stroke, hazard ratio, 0.80; 95% CI, 0.73 to 0.88
• ODYSSEY: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab[7].
  • 18,924 subjects 40 years of age or older, hospitalized with an acute coronary syndrome 1 to 12 months before randomization and had an LDL-C of at least 70 mg/dL, a non-HDL-C of at least 100 mg/dL, or an apolipoprotein B level of at least 80 mg/dL.
  • Fifteen percent reduction in the primary endpoint, composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization, hazard ratio, 0.85; 95% CI, 0.78 to 0.93
  • Fifteen percent reduction in the secondary endpoint, any coronary heart disease event, major coronary heart disease events, any cardiovascular event, and a composite of death from any cause, nonfatal myocardial infarction, or nonfatal ischemic stroke, hazard ratio, 0.85; 95% CI, 0.73 to 0.98
  • The absolute benefit was greater among patients who had a baseline LDL-level of greater than or equal to 100 mg/dL

Cost

• Expensive: list price $5,850 a year
• Requires prior authorization
• Generally recommended for patients with established or at high risk for cardiovascular disease who cannot achieve adequate lowering of LDL-cholesterol with maximally tolerated statin ± ezetimibe or who are statin-intolerant

The American College of Cardiology. American Heart Association and the National Lipid Association 2018 published guidelines on the use of PCSK9 inhibitors in adults.

PCSK9 inhibitors are recommended for the following groups:[8]

• Patients with cardiovascular disease at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on a maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable
• Patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be a consideration.
• In patients, 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher (≥5.7 mmol/L) who achieve an on-treatment LDL-C level of 130 mg/dL or higher (≥3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may merit consideration.

The specific details of these guidelines formulated by the ACC and NLA are cited in the references at the end of this article.

Other agents tested or under development

Bococizumab is a humanized monoclonal antibody to PCSK9 that was under development to treat hypercholesterolemia. Researchers discontinued the clinical trials due to the development of anti-drug antibodies that limited its long-term efficacy. In the SPIRE Cardiovascular Outcomes Trials, 48% of subjects receiving bococizumab developed anti-drug antibodies, and 29% of subjects receiving bococizumab developed neutralizing antibodies.[9] Relative LDL-C reduction is highly variable among subjects who do not form anti-drug antibodies to bococizumab.[10] This concern has not been a problem observed in clinical trials with evolocumab or alirocumab.

Treatment with small interfering RNAs (inclisiran) designed to target PCSK9 messenger RNA is under investigation in clinical trials as an alternative mechanism to reduce PCSK9 activity and LDL-cholesterol levels.[11]

Adverse side effects can include[12]:

• Injection-site reactions, generally mild
• Nasopharyngitis
• No increased signal for hepatotoxicity
• No increase in muscle-related complaints or increase in muscle enzymes compared to ezetimibe
• No clinically significant drug-drug interactions
• No increased risk of cognitive impairment 

Alirocumab is contraindicated in patients with a history of hypersensitivity reactions to alirocumab.

Evolocumab is contraindicated in patients with a history of hypersensitivity reactions to evolocumab.