Page 1 of 12
British Journal of Healthcare and Medical Research - Vol. 10, No. 6
Publication Date: December 25, 2023
DOI:10.14738/bjhmr.106.15955.
Bolodeoku, J., Gbaa, T., Morris, K., & Whitehead, S. (2023). Medicine Optimisation Using PCSK9 Monoclonal Antibodies (Alirocumab
and Evolocumab) Concerning the European Atherosclerosis Society (EAS) of < 1.8 mmol/l LDL Cholesterol Target in a Secondary Care
Lipid Clinic. British Journal of Healthcare and Medical Research, Vol - 10(6). 91-102.
Services for Science and Education – United Kingdom
Medicine Optimisation Using PCSK9 Monoclonal Antibodies
(Alirocumab and Evolocumab) Concerning the European
Atherosclerosis Society (EAS) of < 1.8 mmol/l LDL Cholesterol
Target in a Secondary Care Lipid Clinic
J Bolodeoku
Lipid Clinic, Department of Cardiology, Basingstoke and North Hampshire Hospital,
Aldermaston Road, Basingstoke, Hampshire RG24 9NA
T Gbaa
Lipid Clinic, Department of Cardiology, Basingstoke and North Hampshire Hospital,
Aldermaston Road, Basingstoke, Hampshire RG24 9NA
K Morris
Department of Clinical Biochemistry, Basingstoke and North Hampshire Hospital,
Aldermaston Road, Basingstoke, Hampshire RG24 9NA
S Whitehead
Department of Clinical Biochemistry, Basingstoke and North Hampshire Hospital,
Aldermaston Road, Basingstoke, Hampshire RG24 9NA
ABSTRACT
Background and Aims: Proprotein convertase subtilisin kexin type 9 (PCSK9) is an
essential regulator of cholesterol metabolism. It was introduced as a monoclonal
antibody to regulate LDL-R by recycling more LDLR onto the cell's surface. The
clinically available PCSK9 monoclonal antibodies are alirocumab and evolocumab.
This audit-based assessment aims to evaluate the impact of PCSK9 inhibitors on
patient outcomes in achieving the European Atherosclerosis Society (EAS)
recommended target for low-density lipoprotein cholesterol (LDL-C) levels
(<1.8mmol/l) within a secondary care lipid clinic. Methods: This clinic-based,
retrospective case note review assessed adults prescribed PCSK9i monoclonal
antibodies from March 2017 to July 2022 at a secondary referral lipid clinic,
following the ASC/EAS guidelines for LDL-C targets. All adults aged 18 years and
above receiving PCSK9is (specifically, SCI Alirocumab or Evolocumab) were
included, while patients not prescribed PCSK9i and those lacking calculated LDL-C
measurements were excluded from the study. One hundred fifty-one patient files
were assessed, and the most recent LDL-cholesterol data was compiled for 89
patients. Among these, 41 (47%) were male and 47 (53%) were female, aged 38 to
82. Age groups were categorised as follows: 38-46.6 years (8%), 46.6-55.2 years
(22%), 55.2-63.8 years (20%), 63.8-72.4 years (25%), and 72.4-81 years (25%),
with a mean age of 62.4 years. Results: The overall percentage of patients who
achieved the ESC/EAS guideline-recommended LDL-cholesterol levels of <1.4
mmol/L and <1.8 mmol/L after adding PCSK9 monoclonal antibodies were 18% and
Page 2 of 12
92
British Journal of Healthcare and Medical Research (BJHMR) Vol 10, Issue 6, December- 2023
Services for Science and Education – United Kingdom
35%, respectively. 26 patients (29%) were at target (=/<1.8 mmol/L), of which 24
(77%) were on Praluent (5 were on Praluent 75mg) whilst 7 (23%) were on
Repatha 140mg. 58 patients [23 men and 35 women] (65%) were not at target (>1.8
mmol/L), of which 38 (77%) were on Praluent (8 were on Praluent 75mg) whilst 19
(33%) were on Repatha 140mg. Most of the patients on PCSK9mAb tolerated the
injects. However, 11 (12%) of the 89 patients were switched from one PCSK9mAb
to another and 9 (10%) were discontinued from being administered a PCSK9mAb
for various reasons. Conclusion: This real-world study highlights the impact of
PCSK9 monoclonal antibodies (mAb) on reducing LDL-C levels in dyslipidaemia
patients. While acknowledging the potential differences in real-world patient
responses compared to clinical trials due to individual variations in drug
metabolism and genetics, these findings encourage healthcare providers to explore
using these newer agents alongside or as an alternative to statins. This strategy
effectively lowers LDL-C levels to meet guideline recommendations, ultimately
reducing the risk of cardiovascular disease.
Keywords: LDL-cholesterol, PCSK9 Inhibitors, Alirocumab, Evolocumab, Secondary care
lipid clinic, Monoclonal antibodies
INTRODUCTION
Cholesterol is crucial in maintaining normal cell function and is a precursor for producing
steroid hormones and bile acids. Research has demonstrated that lowering LDL-C levels,
typically achieved using statins, significantly reduces cardiovascular disease (CVD) events.
Nevertheless, statin therapy alone proves insufficient in effectively lowering LDL-C levels for
numerous patients, particularly those diagnosed with familial hypercholesterolemia.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an essential regulator of cholesterol
metabolism. Based on its activity, its circulating concentrations could affect low-density
lipoprotein cholesterol (LDL-C) levels by regulating Low-density lipoprotein receptor (LDL-R),
it has been implicated as a genetic cause of familial hypercholesterolemia. Due to its role in the
degradation and recycling of LDL-C receptor levels (Figure 1), it has been proposed and used
as a newer lipid-lowering drug in the form of a monoclonal antibody inhibiting the activity of
PCSK9. The action of these monoclonal antibodies is shown in Figure 1.
Fig 1: The degradation and recycling of LDLR
Page 3 of 12
93
Bolodeoku, J., Gbaa, T., Morris, K., & Whitehead, S. (2023). Medicine Optimisation Using PCSK9 Monoclonal Antibodies (Alirocumab and
Evolocumab) Concerning the European Atherosclerosis Society (EAS) of < 1.8 mmol/l LDL Cholesterol Target in a Secondary Care Lipid Clinic. British
Journal of Healthcare and Medical Research, Vol - 10(6). 91-102.
URL: http://dx.doi.org/10.14738/bjhmr.106.15955.
A. The mechanism of the degradation and recycling of LDLR: LDLR binds the LDL particle through an
endocytotic process, in which both the LDLR and LDL particle are separated in the endosome, and the
LDLR is recycled back to the cell surface.
B. PCSK9 binds both the LDLR and LDL particles, degrading them both without recycling LDLR back to the
cell surface.
Monoclonal antibodies targeting PCSK9 (PCSK9mAb) have demonstrated the ability to reduce
plasma LDL-C levels by approximately 60%, even in individuals already on maximum-dose
statin therapy (Sabatine, 2018) (1). It has been shown that individuals with lower activity of
PCSK9, due to monoclonal antibodies to PCSK9 or genetic polymorphism, have lower
circulating LDL-C and a better cardiovascular disease risk (Ji and Lee, 2021) (2). Two injectable
monoclonal antibodies are Alirocumab (Praluent) and Evolocumab (Repatha), currently
prescribed by lipid specialists. PCSK9 mAbs have been introduced into our armamentarium of
lipid-lowering treatments in getting our patients towards optimal treatment targets. A recent
audit of PCSK9 mAbs and treatment targets showed that 46% of the patients achieved an LDL- cholesterol concentration of < 1.8 mmol/l and 24% of the patients achieved an LDL-cholesterol
concentration of < 1.4 mmol/l (Suresh et al., 2022) (3).
Fig 2: Mechanism of Action of Monoclonal Antibody Inhibitors Targeting PCSK9
PCSK9 Monoclonal antibodies (Alirocumab and Evolocumab) bind the PCSK9, freeing up more
LDL-R receptors during the recycling to attach and remove excess LDL from the blood and
circulation.