There are two available PCSK9 inhibitors: Alirocumab and Evolocumab.
FDA has approved Alirocumab for adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD who require further lowering of LDL-cholesterol in addition to diet modification and maximally tolerated statin therapy.
FDA has approved Evolocumab for adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD who require further lowering of LDL-cholesterol in addition to diet modification and maximally tolerated statin therapy. It also is approved for adult patients with homozygous familial hypercholesterolemia who require further lowering of LDL-C in addition to other LDL-lowering therapies like statins, ezetimibe, or LDL apheresis.
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.
A decrease in the activity of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis.
The activation of ACAT, an enzyme that increases the storage cholesterol as cholesterol ester.
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 are continually recycled 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 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 is diminished by 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 genetic mutation of the LDL receptor, rarely a mutation of the apoprotein B100 gene. In 2003, a family in France was found to have the familial hypercholesterolemia phenotype without 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 is sustained as long as treatment continues.
Supplied in 75 mg or 150 mg single-dose pre-filled pen or syringe.
The recommended starting dose is 75 mg once every 2 weeks administered subcutaneously.
An alternative starting dose is 300 mg once 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.
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 2 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 needed for patients with mild or moderately impaired hepatic or renal function. No data are available in patients with severe hepatic or renal impairment.
Decrease LDL-cholesterol 45-70%
Decrease apoprotein B 40-50%
Decrease lipoprotein (a) 30-35%
Decrease triglyceride 8-10%
Increase HDL-cholesterol 8-10%
Increase apoprotein A1 4-5%
Early, short-term studies (52 to 84 weeks), along with a 4-year-long study (OSLER-1), have suggested a significant reduction in cardiovascular events.
Intravascular ultrasound evidence of plaque regression in patients on PCSK9 inhibitors (GLAGOV study).
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.
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 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
Ongoing trial of 18,600 subjects randomized to alirocumab or placebo after ACS
Data expected in December 2017
Very expensive: $14,000 to $15,000 a year
Requires prior approval
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
Recently, The American College of Cardiology (2016) and the National Lipid Association (2017) published updates on the use of PCSK9 inhibitors in adults.
PCSK9 inhibitors are recommended for the following groups:
Adults with clinical ASCVD who cannot achieve an adequate lowering of their LDL-C on maximally tolerated statins ± ezetimibe.
Adults without clinical ASCVD who cannot achieve an adequate lowering of their LDL-C on maximally tolerated statins.
Adults with LDL-C =190 mg/dL who cannot achieve an adequate lowering of their LDL-C on maximally tolerated statins ± ezetimibe.
Statin intolerant patients at very-high-risk for a vascular event patients who require substantial lowering of their LDL-C despite the use of other lipid-lowering therapies.
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 monoclonal antibody to PCSK9 that was under development to treat hypercholesterolemia. Clinical trials were discontinued due to the development of anti-drug antibodies that limited its long-term efficacy. This has not been a problem observed in clinical trials with evolocumab or alirocumab.
Treatment with small interfering RNA (inclisiran) designed to target PCSK9 messenger RNA are being tested in clinical trials as an alternative mechanism to reduce PCSK9 activity and LDL-cholesterol levels.
Adverse side effects can include:
Injection-site reactions, generally mild
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
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.
An LDL-C should be rechecked after starting treatment with alirocumab or evolocumab.
Alirocumab usually is started at a dose of 75 mg every 2 weeks. After 4-8 weeks repeat an LDL-C level. If the LDL-C response is not adequate, increase to the maximum dose of 150 mg every 2 weeks. Following the dose adjustment, remeasure an LDL-C after 4 to 8 weeks.
Patients taking alirocumab or evolocumab. An interdisciplinary team of the clinician and nurse should work with the patient to assure regular followup and reevaluation to obtain the optimal dose. [Level V]
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|||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]|
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|||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]|
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|||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]|