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Proprotein convertase subtilisin/kexin type
9 inhibitors (PCSK9I)
Sio-pan Chan 陳少斌,Wilbert WB Wong 王維斌,Alfred KY Tang 鄧權恩
Proprotein convertase subtilisin kexin 9 (PCSK9)
is a natural protein mostly found in the liver. It plays a
key role in plasma cholesterol metabolism.
In 2011, the first study on PCSK9 was published
by Canadian researchers on the loss-of-function
mutation P CS K9 gene s pecific to a few F rench
Canadian families. Such mutation was generally
associated with significant longevity with a much lower
incidence of cardiovascular diseases than average.
Typically people with such mutations have very low
levels of LDL cholesterol and are leading otherwise
completely normal lives. Further studies revealed that
the gene encoding PCSK9 is highly polymorphic.
Two categories of PCSK9 sequence variant produce
mild to moderate (and opposing) phenotypes. Gain-of-function sequence variant cause a reduction in
the Low Density Lipoprotein Receptor (LDL-R) that
leads to hypercholesterolaemia or autosomal dominant
hypercholesterolaemia in severe phenotypic variants.
PCSK9 loss-of-function sequence variant decrease
LDLR degradation, thereby reducing LDL cholesterol
(LDL-C) concentrations.
Pharmaceutics companies soon developed specific
monoclonal antibodies to block the function of PCSK9
protein, which was shown to be working wonders in
lowering LDL-C, by as much as 60% and without
much apparent side effects. It can be used alone or in combination with other standard cholesterol
lowering medication such as statins and ezetimibe. It is
particularly suitable for secondary prevention in patients
who are statin intolerant, or when maximum standard
oral treatment fails to achieve treatment target.
PCSK9 Inhibitors (PCSK9I) utilise a completely
different mechanism from statins, they do not involve
the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA)
pathway. Theoretically they do not share the side
effects of statin, such as CoQ10 depletion. PCSK9I
are monoclonal antibodies so they are really a kind of
targeted or gene therapy. The main drawbacks are cost
and the need for subcutaneous injection.
However, the whole idea of using PCSK9I
treatment is based on the “dogma” that lowering
LDL-C will reduce cardiovascular disease, as we have
discussed in our previous article “The cholesterol and
stain controversy' (The Hong Kong Practitioners, March
2023 issue), the lipid hypothesis in atherosclerosis
pathogenesis is still controversial and far from being
settled. PCSK9Is were only marketed in 2015, present
data suggests they are highly effective in lowering
LDL-C and in secondary prevention of CVD. It is far
too early to tell the long term side effects of very low
LDL-C. A reanalysis was published in January 2023
on an important trial which raised safety concerns and
efficacy of the results from FOURIER cardiovascular
outcomes trial. This trial was one of the key trials for
the approval of evolocumab, one of the two PCSKI
on the market. After re-adjudication, deaths of cardiac
origin were numerically higher in the evolocumab
group than in the placebo group in the FOURIER
trial, suggesting possible cardiac harm. Perhaps the
true efficacy of PCSK9I and whether their high cost is
justifiable remain to be seen. As a cautionary tale, we
also did a search on the internet on the possible harmful effects of a very low level of LDL-C. They include
haemorrhagic stroke, cancer and infectious diseases,
references of which will be given below.
An update on the role of PCSK9 in atherosclerosis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508721/
Atherosclerosis is initiated by functional changes in
the endothelium accompanied by accumulation, oxidation,
and glycation of LDL-cholesterol in the inner layer of
the arterial wall and continues with the expression of
adhesion molecules and release of chemoattractants.
PCSK9 is a proprotein convertase that increases
circulating LDL levels by directing hepatic LDL
receptors into lysosomes for degradation. The effects of
PCSK9 on hepatic LDL receptors and contribution to
atherosclerosis via the induction of hyperlipidaemia are
well defined. Monoclonal PCSK9 antibodies that block
the effects of PCSK9 on LDL receptors demonstrated
beneficial results in cardiovascular outcome trials. This
review focuses on the molecular roles of PCSK9 in
atherosclerotic plaque formation.
PCSK9 inhibitors and ezetimibe with or without
statin therapy for cardiovascular risk reduction:
a systematic review and network meta-analysis
https://www.bmj.com/content/377/bmj-2021-069116.long
The aim of this article was to compare the impact
of ezetimibe and proprotein convertase subtilisin/kexin
type 9 (PCSK9) inhibitors on cardiovascular outcomes
in adults taking maximally tolerated statin therapy or
those who are statin intolerant. The authors identified
14 trials assessing ezetimibe and PCSK9 inhibitors
among 83 660 adults using statins. They concluded that
Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI
and stroke in adults at very high or high cardiovascular
risk who are receiving maximally tolerated statin
therapy or are statin-intolerant, but not in those with
moderate and low cardiovascular risk.
Effect of PCSK9 inhibitors on clinical outcomes
in patients with hypercholesterolaemia: A meta- analysis
of 35 randomised controlled trials
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779013/
The aim of this article is to examine the efficacy
and safety of two PCSK9 (proprotein convertase
subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. A systematic review and meta-analysis of
randomised controlled trials comparing treatment with
and without PCSK9 inhibitors; 35 randomised controlled
trials comprising 45,539 patients (mean follow-up: 85.5
weeks) were included.
The authors concluded that treatment with a
PCSK9 inhibitor was well tolerated and improved
cardiovascular outcomes. Although no overall benefit
was noted in all-cause or cardiovascular mortality, such
benefit may be seen in patients with higher baseline
low-density lipoprotein cholesterol.
Evolocumab and clinical outcomes in patients with
cardiovascular disease
https://www.nejm.org/doi/full/10.1056/nejmoa1615664
This paper concluded that at 48 weeks, the mean
percentage reduction in LDL cholesterol levels with
evolocumab, as compared with placebo, was 59%.
Relative to placebo, evolocumab treatment significantly
reduced the risk of the primary end point (1344 patients
[9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95%
confidence interval (CI), 0.79 to 0.92; P < 0.001) and the
key secondary end point (816 [5.9%] vs. 1013 [7.4%];
hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P < 0.001).
Cognitive function in a randomised trial of
evolocumab
https://www.nejm.org/doi/full/10.1056/nejmoa1701131
In a randomised trial involving patients who
received either evolocumab or placebo in addition to
statin therapy, no significant between-group difference
in cognitive function was observed over a median of 19
months. However, we think that the trial period of 19
months was probably far too short to make a definitive
conclusion on such an important issue.
Restoring mortality data in the FOURIER
cardiovascular outcomes trial of evolocumab in
patients with cardiovascular disease: a reanalysis
based on regulatory data.
https://bmjopen.bmj.com/content/12/12/e060172
The authors concluded “After re-adjudication,
deaths of cardiac origin were numerically higher in
the evolocumab group than in the placebo group in the
FOURIER trial, suggesting possible cardiac harm. At the
time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed
with evolocumab, which was numerically greater in our
re-adjudication. A complete restoration of the FOURIER
trial data is required. In the meantime, clinicians should
be sceptical about prescribing evolocumab for patients
with established atherosclerotic cardiovascular disease.”
Low-density lipoprotein cholesterol and risk of
intracerebral haemorrhage: A prospective study
https://pubmed.ncbi.nlm.nih.gov/31266905/
The authors in this paper concluded that there is
a significant association between lower LDL-C and
higher risk of ICH when LDL-C was < 1.8mmol/L.
The association became nonsignificant when LDL-C ≥
1.8mmol/L. These data can help in the determination
of the ideal LDL range in patients who are at increased
risk of both atherosclerotic disease and haemorrhagic
stroke, and guide the planning of future lipid-lowering
studies. The level of LDL-C achieved by PCSK9I is far
below 1.8mmol/L.
Low serum LDL cholesterol levels and the risk
of fever, sepsis, and malignancy
https://pubmed.ncbi.nlm.nih.gov/18000291/
The authors investigated the association of low
serum LDL cholesterol levels (< or = 70 mg/dl) and
the incidences of fever, sepsis, and malignancy. A
retrospective analysis of 203 patients' charts was
carried out. The result demonstrated increased odds of
haematological cancer with LDL-C < 70mg/dl by more
than 15-fold (OR 15.7, 95% CI 1.78-138.4, p = 0.01).
Each 1 mg/dl increase in LDL was associated with a
relative reduction of 2.4% in the odds of haematological
cancer (OR 0.976, 95% CI 0.956-0.997, p = 0.026).
Low LDL levels also increased the odds of fever and
sepsis. In summary, low serum LDL cholesterol level
was associated with increased risks of haematological
cancer, fever, and sepsis. This study was published
before the introduction of PCSK9I.
Sio-pan Chan, MBBS (HK), DFM (HKCU), FHKFP, FHKAM (Family Medicine)
Family Physician in private practice
Wilbert WB Wong,FRACGP, FHKCFP, Dip Ger MedRCPS (Glasg), PgDipPD (Cardiff)
Family Physician in private practice
Alfred KY Tang,MBBS (HK), MFM (Monash)
Family Physician in private practice
Correspondence to: Dr Sio-pan Chan, SureCare Medical Centre (CWB), Room 1116-7,
11/F, East Point Centre, 555 Hennessy Road, Causeway Bay,
Hong Kong SAR.
E-mail: siopanc@gmail.com
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