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Reviews in Cardiovascular Medicine  2019, Vol. 20 Issue (1): 1-8     DOI: 10.31083/j.rcm.2019.01.31812
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A short review of proprotein convertase subtilisin/kexin type 9 inhibitors
Rudaynah A. Alali1, *()
1Department of Internal Medicine, King Fahd Hospital of the University, Alkhobar, College of Medicine, Imam Abdulrahman bin Faisal University 31441, Dammam, Saudi Arabia
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Cardiovascular disease is the leading cause of morbidity and mortality globally, as estimated by the World Health Organization, where in 2016, 15.2 million deaths were attributed to ischemic heart disease and stroke. It is therefore essential to try to reduce the incidence of Cardiovascular disease by controlling modifiable risk factors. One such major modifiable risk factor is cholesterol, which influences the pathogenesis and progression of atherosclerosis. Statins are often prescribed to lower blood levels of low density lipoprotein cholesterol, thereby reducing the risk of Cardiovascular disease by approximately 25-35%. However, there is an increasing number of patients (in particular those with intolerance to statin therapy and those with familial hypercholesterolemia) for whom statin therapy alone is not enough to control low density lipoprotein cholesterol. In this review, the regulation of cholesterol metabolism will be discussed with an emphasis on novel cholesterol lowering drugs used in clinical trials. These second-generation drugs, monoclonal antibodies against the low density lipoprotein receptor gene known as proprotein convertase subtilisin/kexin type 9 inhibitors, are expected to be prescribed to patients who are intolerant to statins, as well as in conjunction with statins. Future perspectives of the clinical use of these drugs is also discussed.

Key words:  Cardiovascular disease      statin      hypercholesterolemia      proprotein convertase subtilisin/kexin type 9 inhibitors     
Published:  30 March 2019     
*Corresponding Author(s):  Rudaynah A. Alali     E-mail:

Cite this article: 

Rudaynah A. Alali. A short review of proprotein convertase subtilisin/kexin type 9 inhibitors. Reviews in Cardiovascular Medicine, 2019, 20(1): 1-8.

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Figure 1.  Mortality as a result of various diseases worldwide, led byischemic heart disease and stroke(Source: Global health estimates 2016: deaths by cause, age, sex, by country and by region, 2000-2016. Geneva, World Health Organization; 2018)

Table 1  Comparison of the three clinical trials of the PCSK9 inhibitors
Type of PCSK9 inhibitor Evolocumab (Fully human monoclonal Ab) Alirocumab (Fully human monoclonal Ab) Bococizumab (Murine-derived Ab)
Timelines Start: Jan. 2013; End: Feb. 2018 Start: Oct. 2012; End: March 2018 Start: Oct. 2013; End: Aug. 2017
Study design Randomized, parallel, double-blind placebo -
Patient type History of clinically evident CVD at high risk for recurrent event ACS within the last 4-52 weeks. History of clinically evident CVD at high risk for recurrent event Subjects at high risk of a CVD event receiving background lipid lowering therapy
Follow up Median 2.2 years Median 2.8 years -
Total patients 22,500 (including 9,000 ≥ 65 years) 18,000 SPIRE-1: 12,000; SPIRE-2: 6,300
LDL-C (mg/dl) on background therapy LDL-C ≥ 70 or Non-HDL-C ≥ 100 LDL-C ≥ 70; Non-HDL-C ≥ 100 or
Apo B ≥ 80
SPIRE-1: LDL-C ≥ 70 & < 100 or
Non-HDL-C > 100 & < 130
SPIRE-2: LDL-C ≥ 100 or
Non-HDL-C ≥ 130
Statin regimen Atorvastatin 20-80 mg or an alternative statin. High dose 69%, Moderate dose 30%, Ezetimibe: 5.1% Atorvastatin 20-80 mg or Rosuvastatin 20-40 mg. High-dose: 89%, Ezetimibe: 3% Not specified
Inhibitor dose 140 mg Q2 weeks or 420 mg Q4 weeks 75 mg or 150 mg Q2 weeks 150 mg Q2 weeks
Mean age 63 years 58 years -
% DM/HTN/Smoking 37% / 80% / 28.2% 29% / 63.3% / 23.9% -
Stroke/PAD history 19.3% / 13.2% 2.9% / 3.7% -
Exclusion criteria ?Myocardial infarction or stroke within 4 weeks
?NYHA class III or IV CHF symptoms or LVEF < 30% or uncontrolled VT
?Planned revascularization within the next 3 months
?Uncontrolled HTN or hemorrhagic stroke
?Organ transplant or major active infection
?Recurrent ACS or coronary revascularization within 2 weeks
?NYHA class III or IV CHF; LVEF < 25%
?Uncontrolled HTN or hemorrhagic stroke
?Fasting TG > 400 mg/dl or use of fibrates other than fenofibrate
?Liver transaminases > 3 x ULN; HBV, HCV infection, CK > 3 x ULN
?Estimated GFR < 30 ml/min/1.73 m2
?Positive pregnancy test
Primary endpoint 5-point MACE: CVS death, non-fatal MI, unstable angina, ischemic stroke & coronary revascularization 4-point MACE: CVS death, non-fatal MI, unstable angina & ischemic stroke CVS death, non-fatal MI, unstable angina, ischemic stroke & coronary revascularization
Major findings/Outcomes Lowered LDL-C by 59%; significantly reduced MACE by 9.8%, relative risk reduction of 15% over 2.2 years and absolute risk reduction of 1.5% Lowered LDL-C by 63% with notable attenuation in reduction to 55% over the course of follow up due to the down titration of Alirocumab dose at low LDL-C levels; The reduction in MACE is also a challenge to interpret due this reason. Lowers LDL-C by 55-60%; significantly reduced CV event rates in the higher-risk SPIRE-2 trial;
Patients developed anti-drug antibodies
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[8] Eli M. Roth, Michael H. Davidson. PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety[J]. Reviews in Cardiovascular Medicine, 2018, 19(S1): 31-46.
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[11] Alberto Palazzuoli, Helen Hashemi, Lauren C. Jameson, Peter A. McCullough. Hyperuricemia and Cardiovascular Disease[J]. Reviews in Cardiovascular Medicine, 2017, 18(4): 134-145.
[12] Claudio Ronco, Federico Ronco, Peter A. McCullough. A Call to Action to Develop Integrated Curricula in Cardiorenal Medicine[J]. Reviews in Cardiovascular Medicine, 2017, 18(3): 93-99.
[13] Jane I. Won, Jun Zhang, Kristen M. Tecson , Peter A. McCullough. Balancing Low-density Lipoprotein Cholesterol Reduction and Hepatotoxicity With Lomitapide Mesylate and Mipomersen in Patients With Homozygous Familial Hypercholesterolemia[J]. Reviews in Cardiovascular Medicine, 2017, 18(1): 21-28.
[14] Seth J. Baum, Daniel Soffe, P. Barton Duell. Emerging Treatments for Heterozygous and Homozygous Familial Hypercholesterolemia[J]. Reviews in Cardiovascular Medicine, 2016, 17(1-2): 16-27.
[15] Boback Ziaeian, John Dinkler, Karol Watson. Implementation of the 2013 American College of Cardiology/American Heart Association Blood Cholesterol Guideline Including Data From the Improved Reduction of Outcomes: Vytorin Efficacy International Trial[J]. Reviews in Cardiovascular Medicine, 2015, 16(2): 125-130.
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