cardiovascular
PCSK9 inhibitors:
hope or hype?
The development of PCSK9 inhibitors is a great example of serendipity,
clever exploitation of a fascinating genetic observation, and rational drug development
using monoclonal antibody technology in the 21st century
Heerajnarain Bulluck
PhD MRCP
Will Davies PhD MRCS
MRCP
Papworth Hospital
NHS Foundation Trust,
Cambridge, UK
Cardiovascular disease (CVD) remains the leading
cause of death worldwide and accounted for up to
a third of all deaths in 2015. 1 The global financial
burden of CVD was estimated to be $863 billion
in 2010, and this is expected to rise by a fifth in
the next decade. 2 The INTERHEART study was
a large study with participants from 52 countries
and it showed that, among all the risk factors
identified, abnormal lipid levels were associated
with the highest population attributable risk
(approximately 50%) for the occurrence of
myocardial infarction. 3 As a result, several studies
targeting a reduction in total cholesterol levels
from 1980 to 2010 showed significant a reduction
(ranging between 19-46%) in coronary heart
disease. 4 Low-density lipoprotein cholesterol (LDL-
C) has now emerged as being more atherogenic
than total cholesterol and is the primary
target for lipid-lowering intervention in most
guidelines. 5–7
Statins are the treatment of choice for reducing
LDL-C. 5–7 However, statins can be diabetogenic
and their side-effects profile may lead to poor
adherence for some patients. Ezetimibe was
developed to address the limitations of statins
and the IMPROVE-IT trial showed that
a combination of ezetimibe and statin led to an
incremental lowering of LDL-C levels and better
cardiovascular outcomes in patients with acute
coronary syndrome. 8
The availability of proprotein convertase
subtilisin/kexin type 9 (PCSK9) inhibitors has
provided us with an additional tool to reduce
LDL-C further, in those with sub-optimal levels
or those intolerant of statins.
We will review the recent rapid rise of PCSK9
inhibitors (Figure 1), the challenges facing their
adoption and future directions to help their
integration in the clinical setting.
PCSK9
PCSK9 is an enzyme secreted by the liver
and it modulates the LDL receptor density on
the surface of hepatocytes. PCSK9 plays an
important role in the regulation of plasma LDL-C
levels. It was originally observed in a study
of a French family with autosomal dominant
hypercholesterolaemia in 2003. 9 Researchers
identified mutations in the PCSK9 gene that were
associated with high levels of LDL-C. Three years
later, these initial observations were subsequently
followed by the documentation of the effect of
PCSK9 polymorphisms on LDL-C levels in the
general population, 10 and the recognition that
figure 1
Timeline in the developments of PCSK9 inhibitors
First report of famillial
hypercholesterolaemia
due to gain-of-function
mutations in PCSK9
PCSK9 knock-out in animals
shown to decrease LDL-C levels
Phase I trial of
PCSK9 inhibitor in
human reported
Post-hoc and meta
analyses showing
improvement in
clinical outcomes
with PCSK9 inhibitors
Fourier trial
and meta-
analysis showing
improvements in
clinical outcomes
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
PCSK9 first
described
First report of
reduced LDL-C and
cardiovascular risk
in humans with
lost-of-function
mutations in PCSK9
Anti-PCSK9
monoclonal
antibody shown to
decrease LDL-C in
animals
41
HHE 2018 | hospitalhealthcare.com
Safety and
sustained LDL-C
lowering efficacy
demonstrated
over 48–78 weeks
(Odyssey long term
and Olser trials)
Approval of
evolocumab and
alirocumab in the
United States and
Europe