JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES, 2017
VOL. 7, NO. 3, 199–200
https://doi.org/10.1080/20009666.2017.1340732
LETTER TO THE EDITOR
Evolocumab to reduce cardiovascular events: results of the (FOURIER)
multinational trial
Dear Sir,
Proprotein convertase subtilisin-kexin type 9
(PCSK9) is a protease that binds to the extracellular
compartment of the LDL receptor, hence, targeting
the LDL receptor to the lysosomal compartment of
the cell for degradation [1]. Consequently, PCSK9
prevents recycling of the LDL receptor to the cell
surface, thereby modifying LDL clearance. With the
discovery of PCSK9 protein as a potential therapeutic
target, monoclonal antibodies that inhibit PCSK9
action were developed. Studies suggested that both
PCSK9-inhibitors and statins treatment lower LDL
cholesterol levels with a partly similar mechanism of
action. As such, evolocumab, a monoclonal antibody
against the PCSK9, has been extensively tested. In
two open-label, randomized extension studies (Open
Label Study of Long Term Evaluation Against LDL-C
Trial [OSLER]–1 and OSLER-2, respectively), evolo-
cumab in addition to standard lipid-lowering therapy
elicited a sustained 61% reduction in LDL cholesterol
levels (relative to the change in LDL cholesterol levels
with standard therapy alone) [2].
Sabatine et al. now report the results of the Further
Cardiovascular Outcomes Research with PCSK9
Inhibition in Subjects with Elevated Risk (FOURIER)
multinational trial, which determined the efficacy of
evolocumab (in the same dose regimens as in the
OSLER trials) with regard to cardiovascular events in
27 564 high-risk patients who were followed for a
median of 2.2 years (as compared to 11 months in
OSLER trial) [3]. The mean decrease in LDL choles-
terol levels, as compared with a placebo, was 59% at
48 weeks; this result was paralleled by reductions in
levels of non–high-density lipoprotein (HDL) choles-
terol (decrease of 51% in the evolocumab group),
apolipoprotein B (46%), and triglycerides (16%),
together with relatively small increases in HDL cho-
lesterol (8%). The primary end point, a composite of
cardiovascular death, myocardial infarction, stroke,
hospitalization for unstable angina, or coronary revas-
cularization, occurred in 9.8% of evolocumab-treated
patients, as compared with 11.3% of patients who
received a matching placebo, which corresponded to
a 15% risk reduction. In addition, a 20% risk reduction
© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/),
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
was achieved with respect to the key secondary efficacy
end point, a composite of cardiovascular death, myo-
cardial infarction, or stroke. Remarkably, a reduction
in cardiovascular risk was already seen after one year
of active treatment [4].
The FOURIER trial is a landmark trial providing
formal evidence that treatment targeted at PCSK9
inhibition confers additional cardiovascular benefit
beyond that achieved by lipid-lowering treatment
alone. However, in this trial, the duration of evolocu-
mab treatment was rather short. The efficacy, with
regard to cardiovascular disease, of PCSK9 inhibition
treatment that is started shortly after an acute event
still needs to be determined, as does the efficacy of the
treatment in other categories of high-risk patients. The
side effects of treatment with monoclonal antibodies
against PCSK9 appear to be generally mild but are
being meticulously evaluated in separate sub-studies.
In 2015, the FDA approved the use of evolocumab for
the treatment of certain patients with high cholesterol. It
is anticipated that the results of the FOURIER trial will
soon be implemented in international guidelines regard-
ing the treatment of high-risk patients, directing clini-
cians in the use of this new and expensive class of
drugs [5].
Syed Raza Shah
North Florida Regional Medical Center,
University of Central Florida, Gainesville, USA
syedraza91shah@live.com
Mohd Faisal Uddin
Deccan College of Medical Sciences,
Hyderabad, India
Noman Lateef
Dow University of Health Sciences (DUHS),
Karachi, Pakistan
Amin Muhammad Dharani
Dow University of Health Sciences (DUHS),
Karachi, Pakistan
Waqas Shahnawaz
Agha Khan University Hospital,
Karachi, Pakistan
200 S. R. SHAH

Ahmed Nabeel Kazi [2] Sabatine MS, Giugliano RP, Wiviott SD, et al.
Chandka Medical College, Efficacy and safety of evolocumab in reducing lipids
Larkana, Pakistan and cardiovascular events. N Engl J Med.
2015;372:1500–1509.
[3] Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab
Syed Arbab Shah and clinical outcomes in patients with cardiovascular
Ziauddin Medical University Hospital, disease. N Engl J Med. 2017;376:1713-1722. DOI:10.1056/
Karachi, Pakistan NEJMoa1615664
[4] Shah SR, Fatima K, Ansari M. Recovery of myofilament
function through reactivation of glycogen synthase kinase
3β (GSK-3β): mechanism for cardiac resynchronization
Disclosure statement therapy. J Interv Card Electrophysiol. 2014 Dec;41
(3):193–194. Epub 2014 Sep 26. DOI:10.1007/s10840-014-
No potential conflict of interest was reported by the author. 9939-2
[5] Landmesser U, John Chapman M, Farnier M, et al.
European society of cardiology/European atherosclero-
References sis society task force consensus statement on propro-
tein convertase subtilisin/kexin type 9 inhibitors:
[1] Marais DA, Blom DJ, Petrides F, et al. Proprotein conver- practical guidance for use in patients at very high
tase subtilisin/kexin type 9 inhibition. Curr Opin Lipidol. cardiovascular risk. Eur Heart J. 2016 October 27;
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