There are two PCSK9 inhibitors available in the U.S.: alirocumab and evolocumab.
FDA has approved alirocumab for adult patients:
FDA has approved evolocumab for adult patients:
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.
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.
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.
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.
Both short and long-term studies have shown a significant reduction in cardiovascular events.
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:
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. Relative LDL-C reduction is highly variable among subjects who do not form anti-drug antibodies to bococizumab. 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.
Adverse side effects can include:
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.
The prescriber should recheck the LDL-C after starting treatment with alirocumab or evolocumab.
Alirocumab usually is started at a dose of 75 mg every two weeks. After 4 to 8 weeks, repeat an LDL-C level. If the LDL-C response is not adequate, increase to the maximum dose of 150 mg every two weeks. Following the dose adjustment, remeasure the LDL-C level after 4 to 8 weeks.
Due to the cost associated with a PCSK9 inhibitor, collaboration among physicians, clinical pharmacists, and specialty pharmacies is essential to ensure patient adherence to therapy. For example, interprofessional team members may be required to complete financial assistance paperwork, submit a prior authorization, or obtain a manufacturer discount card for the patient to be able to start therapy. To successfully administer this drug safely, a specialty-trained nurse, pharmacist, and clinician must work as a team and be responsible for ensuring appropriate PCSK9 inhibitor administration techniques, monitoring of laboratory values and adverse effects, and dosing as well as appropriate education of the patient and family. The pharmacist (including board-certified cardiology specialized pharmacists) can consult with the prescriber regarding dosing and proper administration intervals. By using this type of interprofessional team paradigm, these new agents can achieve their intended therapeutic goals for patients, particularly those who are unsuccessful on statin therapy. [Level 5]
|||Update on the use of PCSK9 inhibitors in adults: Recommendations from an Expert Panel of the National Lipid Association., Orringer CE,Jacobson TA,Saseen JJ,Brown AS,Gotto AM,Ross JL,Underberg JA,, Journal of clinical lipidology, 2017 May 19 [PubMed PMID: 28532784]|
|||Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data., Durairaj A,Sabates A,Nieves J,Moraes B,Baum S,, Current treatment options in cardiovascular medicine, 2017 Aug [PubMed PMID: 28639183]|
|||Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab., Stroes E,Colquhoun D,Sullivan D,Civeira F,Rosenson RS,Watts GF,Bruckert E,Cho L,Dent R,Knusel B,Xue A,Scott R,Wasserman SM,Rocco M,, Journal of the American College of Cardiology, 2014 Jun 17 [PubMed PMID: 24694531]|
|||Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study., Koren MJ,Sabatine MS,Giugliano RP,Langslet G,Wiviott SD,Kassahun H,Ruzza A,Ma Y,Somaratne R,Raal FJ,, JAMA cardiology, 2017 Jun 1 [PubMed PMID: 28291870]|
|||Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial., Nicholls SJ,Puri R,Anderson T,Ballantyne CM,Cho L,Kastelein JJ,Koenig W,Somaratne R,Kassahun H,Yang J,Wasserman SM,Scott R,Ungi I,Podolec J,Ophuis AO,Cornel JH,Borgman M,Brennan DM,Nissen SE,, JAMA, 2016 Dec 13 [PubMed PMID: 27846344]|
|||Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease., Sabatine MS,Giugliano RP,Keech AC,Honarpour N,Wiviott SD,Murphy SA,Kuder JF,Wang H,Liu T,Wasserman SM,Sever PS,Pedersen TR,, The New England journal of medicine, 2017 May 4 [PubMed PMID: 28304224]|
|||Schwartz GG,Steg PG,Szarek M,Bhatt DL,Bittner VA,Diaz R,Edelberg JM,Goodman SG,Hanotin C,Harrington RA,Jukema JW,Lecorps G,Mahaffey KW,Moryusef A,Pordy R,Quintero K,Roe MT,Sasiela WJ,Tamby JF,Tricoci P,White HD,Zeiher AM, Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. The New England journal of medicine. 2018 Nov 29 [PubMed PMID: 30403574]|
|||Grundy SM,Stone NJ,Bailey AL,Beam C,Birtcher KK,Blumenthal RS,Braun LT,de Ferranti S,Faiella-Tommasino J,Forman DE,Goldberg R,Heidenreich PA,Hlatky MA,Jones DW,Lloyd-Jones D,Lopez-Pajares N,Ndumele CE,Orringer CE,Peralta CA,Saseen JJ,Smith SC Jr,Sperling L,Virani SS,Yeboah J, 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18 [PubMed PMID: 30565953]|
|||Ridker PM,Amarenco P,Brunell R,Glynn RJ,Jukema JW,Kastelein JJ,Koenig W,Nissen S,Revkin J,Santos RD,Schwartz PF,Yunis C,Tardif JC, Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials. American heart journal. 2016 Aug [PubMed PMID: 27502861]|
|||Ridker PM,Tardif JC,Amarenco P,Duggan W,Glynn RJ,Jukema JW,Kastelein JJP,Kim AM,Koenig W,Nissen S,Revkin J,Rose LM,Santos RD,Schwartz PF,Shear CL,Yunis C, Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab. The New England journal of medicine. 2017 Apr 20 [PubMed PMID: 28304227]|
|||Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol., Ray KK,Landmesser U,Leiter LA,Kallend D,Dufour R,Karakas M,Hall T,Troquay RP,Turner T,Visseren FL,Wijngaard P,Wright RS,Kastelein JJ,, The New England journal of medicine, 2017 Apr 13 [PubMed PMID: 28306389]|
|||Giugliano RP,Mach F,Zavitz K,Kurtz C,Im K,Kanevsky E,Schneider J,Wang H,Keech A,Pedersen TR,Sabatine MS,Sever PS,Robinson JG,Honarpour N,Wasserman SM,Ott BR, Cognitive Function in a Randomized Trial of Evolocumab. The New England journal of medicine. 2017 Aug 17 [PubMed PMID: 28813214]|
|||Atanda A,Shapiro NL,Stubbings J,Groo V, Implementation of a New Clinic-Based, Pharmacist-Managed PCSK9 Inhibitor Consultation Service. Journal of managed care & specialty pharmacy. 2017 Sep [PubMed PMID: 28854074]|
|||Kaufman TM,Warden BA,Minnier J,Miles JR,Duell PB,Purnell JQ,Wojcik C,Fazio S,Shapiro MD, Application of PCSK9 Inhibitors in Practice. Circulation research. 2019 Jan 4 [PubMed PMID: 30605414]|