PCSK9 Inhibitors

Mechanism of Action

PCSK9 has emerged as an important regulator of cholesterol metabolism.[2] Increased PCSK9 activity correlates with heightened LDL-C levels, while specific gain-of-function mutations lead to autosomal dominant familial hypercholesterolemia characterized by extremely high total and LDL-C levels, premature atherosclerotic vascular disease, and the formation of tendon xanthomas.[6][7] Conversely, individuals with reduced PCSK9 activity, whether due to genetic polymorphism or the administration of PCSK9 monoclonal antibodies, exhibit lower cholesterol levels and a reduced risk of cardiovascular disease.[8]

Normal Cholesterol Metabolism

LDL-C is normally cleared from the circulation as apoprotein B100 on the surface of LDL and binds to LDL receptors on hepatic and extrahepatic tissues. LDL bound to these 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, 3 events occur, as mentioned below.[9]

• Decreased activity of 3-hydroxy-3-methylglutaryl coenzyme AHMG-CoA reductase—the rate-limiting enzyme of cholesterol synthesis.

• Activation of acyl-coenzyme A:cholesterol acyltransferase (ACAT)—an enzyme that increases cholesterol storage as a cholesterol ester.

• 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 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 bind and clear more LDL-C. PCSK9, a product of hepatocytes, is secreted into the plasma, where it binds to the LDL receptors, facilitating their lysosomal degradation. Thus, PCSK9 reduces the expression of LDL receptors on the cell membrane, decreasing the clearance of LDL-C.

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-C by the non-atherogenic receptor-mediated pathway, leaving less LDL to be taken up by the scavenger pathway. Statins increase the activity of PCSK9. While statins effectively decrease cholesterol levels, their efficacy is diminished by this increase in PCSK9 activity.

PCSK9

Familial hypercholesterolemia is characterized by high total and LDL-C levels, premature vascular disease, and tendon xanthomas. In most cases, this is due to a genetic mutation of the LDL receptor caused by mutations of the apoprotein B100 or PCSK9 genes. In 2003, researchers reported a family in France with the familial hypercholesterolemia phenotype without an identifiable mutation of the LDL receptor or apoprotein B100.[10] Affected family members were discovered to have a gain of function mutation of a serine protease, PCSK9. Transgenic mice overexpressing PCSK9 have reduced LDL-R function and elevated LDL, while PCSK9 knockout mice have increased LDL-R activity and low LDL-C levels. A longitudinal epidemiologic study found subjects with loss of function mutations in PCSK9 had a modest reduction in LDL-C but a more significant decrease in coronary heart disease.[11]

Understanding these basic principles of cholesterol metabolism led to the hypothesis that measures to reduce PCSK9 activity would lower LDL-C levels and possibly reduce the risk of cardiovascular disease. Three pharmaceutical products in the United States reduce PCSK9 activity: alirocumab, evolocumab, and inclisiran. Alirocumab and evolocumab are fully humanized monoclonal antibodies injected subcutaneously at intervals every 2 to 4 weeks, effectively lowering total and LDL-C. Whether used as monotherapy or combined with a statin, they typically reduce LDL-C levels by 50% to 60%. The effect is sustained as long as treatment continues.[12][13][14] Inclisiran is a small interfering mRNA that inhibits the intracellular synthesis of PCSK9. When administered to patients on maximally tolerated statin therapy, inclisiran reduces LDL-C by 50%.[4][5]

Administration

Available Dosage Forms, Strengths, and Dosages

Alirocumab: Alirocumab offers flexible dosing options, as mentioned below.

• Alirocumab is supplied in a 75- or 150-mg single-dose prefilled pen.

• The recommended starting dosage is 75 mg every 2 weeks, administered subcutaneously.

• An alternative starting dosage regimen is 300 mg every 4 weeks.

• If the LDL-C response is inadequate, the dosage may be adjusted to the maximum dosage of 150 mg administered every 2 weeks.

• No pediatric dosing is recommended for this drug.

 Evolocumab: Evolocumab offers flexible dosing options, as mentioned below.

• Evolocumab is supplied as a 140 mg/mL single-use prefilled syringe or autoinjector and a 420 mg/3.5 mL solution in a single-use infusor with a prefilled cartridge.

• For adults, the dosing is 140 mg every 2 weeks or 420 mg monthly, administered subcutaneously.

• The 420 mg dose can be administered over 5 minutes using the single-use infusor or by consecutively giving 3 140 mg injections within 30 minutes.

• For children aged 10 and older with heterozygous familial hypercholesterolemia, dosing is 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously monthly.

• For adults and children aged 10 and older with homozygous familial hypercholesterolemia, the dosage is 420 mg subcutaneously monthly but can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks.

Inclisiran: The recommended dosage option for inclisiran is mentioned below.

• Inclisiran is supplied in a 284 mg/1.5 mL prefilled syringe.

• The recommended dosage of inclisiran consists of a 284-mg subcutaneous injection initially, followed by a second dose at 3 months, and subsequent doses every 6 months thereafter.

No dosage adjustment is necessary for patients with mild or moderately impaired hepatic or renal function. However, currently, no available data exist on the use of alirocumab, evolocumab, and inclisiran in patients with severe hepatic dysfunction. Specifically for alirocumab, there is a lack of data regarding patients with severe renal impairment, and for inclisiran, data are unavailable for those with end-stage renal disease.

Efficacy of the Drugs

• Decreases LDL-C by 45% to 65%.

• Decreases apoprotein B by 40% to 50%.

• Decreases lipoprotein (a) by 30% to 40%.

• Decreases triglyceride by 8% to 10%.

• Increases HDL cholesterol by 8% to 10%.

• Increases apoprotein A1 by 4% to 5%.[12][15]

Outcomes data

Short- and long-term studies have shown a significant reduction in cardiovascular events with alirocumab and evolocumab.[2][15][16]

Cardiovascular outcomes trials for inclisiran are being conducted, but no published results exist.[5]

• Intravascular ultrasound evidence of plaque regression in patients on PCSK9 inhibitors (GLAGOV study).[17]
  • Decreased plaque volume and plaque regression in a more significant percentage of treated subjects than with placebo.
• Evolocumab versus placebo for 76 weeks.

• FOURIER (evolocumab): Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk.[18]
• Studied 27,564 subjects aged 40 and older or 85 and younger with clinically evident cardiovascular disease at high risk for a recurrent event with LDL-C greater than or equal to 70 mg/dL or non-HDL-C greater than or equal to 100 mg/dL and triglycerides less than or equal to 400 mg/dL.
• 15% reduction in the primary end point, composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, hazard ratio, 0.85; 95% CI, 0.79 to 0.92.
• 20% reduction in the secondary end point of cardiovascular death, MI, or stroke, hazard ratio, 0.80; 95% CI, 0.73 to 0.88.

• ODYSSEY (alirocumab): Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab.[19]
• Studied 18,924 subjects aged 40 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.
• 15% reduction in the primary end point, a 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
• 15% reduction in the secondary end point, and coronary heart disease event, major coronary heart disease events, any cardiovascular event, and a composite of death from any cause, nonfatal MI, or nonfatal ischemic stroke, hazard ratio, 0.85; 95% CI, 0.73 to 0.98.
• The absolute benefit was more significant among patients with a baseline LDL level greater than or equal to 100 mg/dL.

Cost of the Drugs

• The drugs are expensive. In the United States, alirocumab and evolocumab are priced at $5,800 to $6,500 annually, whereas inclisiran costs $9,750 for the first year and $6500 annually thereafter.[2]

• The drugs require prior authorization.

• Generally recommended for patients with established or at high risk for cardiovascular disease who cannot achieve adequate lowering of LDL-C with maximally tolerated statin ± ezetimibe or who are statin-intolerant.

The American College of Cardiology and the National Lipid Association 2022 published guidelines on the use of PCSK9 inhibitors and other nonstatin therapies:

PCSK9 inhibitors are recommended for several patient populations.[15] These include the following:

• In patients with cardiovascular disease at very high risk whose LDL-C level remains ≥55 mg/dL (≥1.42 mmol/L) on a maximally tolerated statin, adding a PCSK9 inhibitor is reasonable.

• In patients with cardiovascular disease not at very high risk whose LDL-C remains ≥70 mg/dL (≥1.81 mmol/L) on a maximally tolerated statin, adding a PCSK9 inhibitor is reasonable.

• In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.91 mmol/L]), without familial hypercholesterolemia, if the LDL-C level on statin ≥70 mg/dL (≥1.81 mmol/L) a PCSK9 inhibitor may be considered.

• In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.91 mmol/L]), with a diagnosis of familial hypercholesterolemia, if the LDL-C level on statin ≥55 mg/dL (≥1.42 mmol/L) a PCSK9 inhibitor may be considered.

• In patients without clinical cardiovascular disease and with baseline LDL-C ≥190 mg/dL on a statin for primary prevention, if the LDL-C level on statin ≥100 mg/dL (≥2.59 mmol/L), a PCSK9 inhibitor may be considered.

• For patients with statin-associated adverse effects, a PCSK9 inhibitor may be considered for those with clinical cardiovascular disease or baseline LDL-C ≥190 mg/dL (≥4.91 mmol/L).

• Inclisiran may be considered in patients who have demonstrated poor adherence to PCSK9 monoclonal antibodies, have adverse effects from both PSCK9 monoclonal antibodies, or cannot adhere to a self-injection regimen.

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

Adverse Effects

Drug-Drug Interactions

Adverse effects for each of these agents are mentioned below.[15][20]

Evolocumab: Evolocumab may lead to severe reactions such as hypersensitivity reactions and angioedema, while common adverse effects encompass injection site reactions, nasopharyngitis, headache, upper respiratory tract infection, musculoskeletal pain, back pain, elevated blood pressure, diarrhea, and myalgia.

Alirocumab: Alirocumab may induce severe reactions such as hypersensitivity reactions, hypersensitivity vasculitis, and angioedema, while common adverse effects include generally mild injection-site reactions, nasopharyngitis, diarrhea, bronchitis, myalgia, muscle spasms, elevated alanine transaminase (ALT) or aspartate transaminase (AST) levels, confusion, and musculoskeletal pain.

Inclisiran: No severe adverse events have yet been reported for inclisiran. Common reactions encompass injection site reactions, arthralgia, urinary tract infections, diarrhea, bronchitis, extremity pain, and dyspnea.

Contraindications

Alirocumab and evolocumab are contraindicated in patients with a history of hypersensitivity reactions to either of the agents. Caution is advised in giving evolocumab to patients with latex hypersensitivity. No contraindications are listed for inclisiran.[15] None of these agents currently have any significant drug-drug interactions listed.[21] 

Monitoring

The prescriber should recheck the LDL-C after starting alirocumab, evolocumab, or inclisiran treatment. Inclisiran is dosed at 284 mg every 6 months. Evolocumab dosing is 140 mg every 2 weeks or 420 mg monthly alirocumab usually is started at a dose of 75 mg every 2 weeks. After 4 to 8 weeks, repeat an LDL-C level. If the LDL-C response is not adequate, increase the dose to a maximum dosage of 150 mg every 2 weeks. Following the dose adjustment, remeasure the LDL-C level after 4 to 8 weeks.[1] 

Enhancing Healthcare Team Outcomes

Due to the cost implications associated with PCSK9 inhibitors and inclisiran, collaborative efforts among clinicians, clinical pharmacists, and specialty pharmacies are paramount to ensure patient adherence to therapy. This collaboration may entail various tasks, such as completing financial assistance paperwork, submitting prior authorizations, or acquiring manufacturer discount cards to facilitate patient access to treatment. A specialized team consisting of nurses, pharmacists, and prescribers must work collectively to ensure the safe administration of these drugs, monitor laboratory values and adverse effects, and provide comprehensive education to patients and their families. Pharmacists, including those specialized in cardiology, can provide valuable insights to prescribers regarding dosing and administration intervals. By leveraging this interprofessional approach, these novel agents can effectively achieve their therapeutic objectives, particularly in patients who have not responded adequately to statin therapy.[22][23]