Vol. 13 Issue 2

Washington University Review of Health Spring 2020
PCSK9 Inhibitors: A Novel Treatment
for High Cholesterol
Writer: Rehan Mehta | Editor: Soyi Sarkar | Illustrator: Parveen Dhanoa
High cholesterol is one of
the most prevalent
health issues in the U.S.
and is a major risk factor for
heart disease, which is the
leading cause of death in this
country. According to the CDC,
about one-third of American adults
have high or borderline high levels
of cholesterol (BRFSS Prevalence &
Trends Data, 2015). Of the three
components of cholesterol— triglycerides,
high-density lipoproteins
and low-density lipoproteins—
high levels of low-density
lipoproteins (LDL) is known to
increase the risk of developing heart
problems. LDL cholesterol is known
as “bad” cholesterol since it can
build up in the walls of arteries,
causing them to become hard and
narrow. This reduces blood flow and
increases the risk of artery blockage,
which can cause a heart attack
or stroke. Current treatments for
high cholesterol, while generally
effective, can cause significant side
effects for many patients. The
development of a new therapeutic
agent, utilizing PCSK9 inhibitors,
has given high hopes to researchers
to address this major concern since
these inhibitors are able to significantly
reduce LDL levels and
potentially reduce the risk of heart
disease.
Currently, statins, a class of cholesterol-lowering
drugs, are prescribed
for people with high cholesterol.
These drugs have been around since
the 1980s and have proven to be
quite reliable and effective for most
people. Despite this, many patients
are unable to reach optimal LDL
cholesterol levels. One study of over
9950 patients with coronary heart
disease revealed that only 37
percent were able to achieve
optimal levels of LDL cholesterol
even though most of them were on
statin therapy (Karalis et al. 2012).
Some patients are unable to achieve
these treatment goals due to factors
that limit the effect of statins in the
body, such as type 2 diabetes, and
adverse effects such as muscle aches
and liver damage, which leads
patients to stop taking statin drugs.
Others, such as those with familial
hypercholesterolemia, a genetic
disorder resulting in high levels of
LDL cholesterol, are likewise unable
to achieve optimal levels of LDL
cholesterol even with high intensity
statin treatment (Chapman, Stock,
& Ginsberg 2015). Due to these
unmet needs, a new treatment is
needed to ensure that optimal LDL
cholesterol levels are attainable.
PCSK9 inhibitors are a new class of
drugs that allow patients to achieve
these optimal LDL levels. PCSK9 is
an enzyme in the liver that binds to
and degrades specific receptors on
the liver cells that are needed to
break down LDL. With less of these
receptors, LDL levels remain high.
PCSK9 inhibitors work by inactivating
the PCSK9 enzyme, resulting in
an increase in receptor availability
which increases capture and break
down of LDL (Do, Vogel, &
Schwartz 2013). There are multiple
approaches that are able to inhibit
the PCSK9 enzyme; however, the
most successful approach has used
monoclonal antibodies. Since the
antibodies in testing are fully
human monoclonal antibodies, the
likelihood that an immune response
occurs in response to the antibody
and the development of antibody
inhibitors is low (Do, Vogel, &
Schwartz 2013). This quality
improves the safety and effectiveness
of this treatment.
The results of several clinical trials
using PCSK9 inhibitors to lower
LDL cholesterol have shown
remarkable success and have
established these inhibitors as a
viable alternative to statins. One
recent phase 3 trial involving 27,564
patients with atherosclerosis, who
were not at optimal LDL cholesterol
levels and were receiving statin
therapy, revealed that the PCSK9
inhibitor reduced LDL cholesterol
levels by approximately 60 percent.
About 87 percent of the patients
were able to achieve optimal LDL
cholesterol levels. PCSK9 inhibitors
were also able to reduce the risk of
heart attack, stroke, and other heart
complications by 21 to 27 percent,
indicating that this therapeutic is
able to reduce the risk of cardiovascular
events. A two year follow-up
further revealed that optimal LDL
cholesterol levels were sustained
(Sabatine et al. 2017). Another
clinical trial evaluating PCSK9
inhibitors in 803 patients with
hypercholesterolemia revealed a
reduction in LDL cholesterol levels
by 52 percent in patients not
receiving statin therapy and 59
percent in patients who were (Roth
et al. 2016). Together, these results
Given the prevalence of high
cholesterol and heart disease, the
development of PCSK9 inhibitors as
a new form of cholesterol manageprovide
evidence of the effectiveness
of PCSK9 inhibitors, especially
in patients who do not respond well
to statins.
The results of these clinical trials
have enabled PCSK9 inhibitors to
gain approval by the FDA and be
available on the market. In 2015, the
FDA approved the first PCSK9
inhibitor alirocumab which was
followed by evolocumab later that
year. Since 2019, both of these drugs
have been approved to prevent
heart attack and stroke (Anderson,
Leigh Ann, ed. 2019). These treatments
would consist of a subcutaneous
injection that can be self-administered
once or twice a month.
Inclisiran, a new PCSK9 inhibitor
still pending approval, would only
need to be taken once or twice a
year (Ray et al. 2020). Statins, on the
other hand, must be taken daily.
Overall, alirocumab and evolocumab
are considered to be quite safe
with only minor side effects, of
which the most common are
redness, pain or itching near the
injection site (Sabatine et al. 2017).
Currently, one of the biggest
limitations to these inhibitors are
their high costs. While prices have
been reduced by 60 percent since
they have been released, they are
still relatively high and cost much
more than statins (Munjal 2019).
The low cost of statins makes it
unlikely that PCSK9 inhibitors will
become the standard of care
anytime soon,
ment is crucial in improving
cardiovascular health and outcomes.
PCSK9 inhibitors represent an
effective treatment addressing the
unmet needs of many patients in
the case where statins have shown
to be ineffective. With PCSK9
inhibitors as a viable alternative to
statins, more patients are able to
achieve optimal LDL cholesterol
levels and maintain their cardiovascular
health. Perhaps in the future,
given further price reductions, these
inhibitors will become the new
standard for lowering cholesterol.
While they might be limited to
certain at risk groups currently,
PCSK9 inhibitors provide a lot of
hope for improving cardiovascular
outcomes in future patient populations.
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