PCSK9 Inhibitors or Cardiovascular Disease Inhibitors?-Juniper Publishers
JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF CARDIOLOGY & CARDIOVASCULAR THERAPY
Cardiovascular disease (CVD) is well documented as
the leading cause of adult mortality and morbidity worldwide and it
remains a substantial public health issue with enormous financial impact
to global economy. Statins remain the cornerstone of lipid management
for both primary and secondary prevention of CVD. A variety of other
lipid modifying therapies are available which can be added to statin
therapy to further reduce CV risk. Nowadays, PCSK9 inhibitors
(evolocumab and alirocumab recently approved) appear promising agents
with multiple trials demonstrating that these agents -in combination
with statins or monotherapy- can modify lipids substantially with an
unprecedented optimal safety profile.
Several large PCSK9 inhibitor clinical outcomes
trials (ODYSSEY-OUTCOMES, FOURIER and the SPIRE-I and II trials) are
currently ongoing, which should elucidate their place in clinical
practice. However, it remains non negotiable that keeping CVD therapy
affordable necessitates restricted use of PCSK9 antibodies to select
patient groups such as Familial Hypercholesterolemia (FH), statin
intolerance and very high CVD risk with residual LDL burden, [1] until
those currently ongoing outcome trials and future randomized survival
trials elucidate the high rank place of these inhibitors in our
cardiovascular armamentarium.
Introduction
Cardiovascular disease (CVD) is well documented as
the leading cause of adult mortality and morbidity worldwide and it
remains a substantial public health issue with enormous financial impact
to global economy. Preventive measures such as reduction of smoking,
blood pressure and atherogenic lipids, as well as advances in treatments
and healthcare have led to large reductions in age-standardized death
rates for CVD, particularly in high income regions [2,3]. However its
prevalence is rising in developing countries [2,3] with all the expected
consequences. The aetiological relationship between long-term average
blood cholesterol concentrations and risk of cardiovascular (CV)
morbidity and mortality has been established reliably by the more than
60 years of evidence from observational, randomized and genetic studies.
Many of the older prospective observational studies which established
these relationships were incorporated into comprehensive meta-analyses
of the lipid risk factors for CVD undertaken by the Emerging Risk
Factors Collaboration (ERFC) [4].
The pooled data from the ERFC observational studies
of about 10 years follow-up shows a hazard ratio of 1.5 (1.39 - 1.61)
per 1 standard deviation (43 mg/dL or 1.1 mmol/L) higher in
non-HDL-cholesterol; whereas more recent Mendelian Randomisation [MR]
studies show that life-long differences in LDL-cholesterol, based on
genetics, are associated with CHD risk even more strongly with about a
2-fold increase in risk per mmol/L higher LDL-C. This indicates
approximately a 3-fold greater reduction in the risk of CHD associated
with a unit lower LDL-C than that observed during treatment with a
statin started later in life [5]. This implies that residual risk
following standard
LDL-lowering treatment may be partly explained by treating late
in the course of the disease, and that earlier treatment would
increase benefit.
The association between non HDL-C and risk of ischaemic
stroke, although also positive, is much less strong although
LDL-C lowering clearly reduces ischaemic stroke in the
randomized trials [4,6]. By contrast, observational data indicates
that HDL-C levels are strongly inversely associated with CHD
and also, although less clearly so, with ischaemic stroke [4].
The positive associations between triglyceride levels and risk
of vascular disease typically disappear on adjustment for the
other lipid factors [4], although recently it has become clear that
remnant cholesterol, the cholesterol content of triglyceride-rich
lipoproteins, is independently associated with CHD even after
adjustment for HDL-C [7,8] and MR studies also support the
importance of triglyceride pathways in CHD risk [9].
In light of these associations, interventions to modify lipids
have been a key component of CVD treatment and prevention.
People whose diet is relatively high in saturated fat can achieve
some reduction in blood cholesterol and LDL-C through dietary
intervention, but this effect is modest [10,11]. Statins are the
cornerstone of lipid modification but, despite intensive statin
therapy, many high risk patients remain at significant risk or
suffer from unsupportable drug-related symptoms. Until today
there were various drug options for the management of this
residual risk through further lipid modification. Nevertheless,
it should be noted that effective CVD reduction strategies need
to adopt a multi-faceted approach to address other major CVD
risk factors, such as blood pressure or diabetes, ensure smoking
cessation and constant physical activity and avoidance of obesity
as well.
Equally, any intervention is only as effective as its
associated compliance, highlighting the importance of patient
understanding of any treatment and its acceptability in clinical
practice. Nevertheless, there are patients in everyday’s clinical
practice who are on maximally tolerated statin therapy and
cannot achieve their attributed specific LDL targets, or even
more, patients intolerant to statins or those patients with
familial hypercholesterolemia,who apparently have unmet need
for lipid lowering therapies beyond statins. PCSK9 inhibitors
such as evolocumab (Repatha, Amgen) and alirocumab
(Praluent, Sanofi/Regeneron) and are potentially good choices
in these populations since the drugs’ effect on LDL reduction is
potent and prolonged and a few associated adverse and post hoc
analyses have shown signals of reduced CV events.
Discovery in 2003 by a company conducting screenings for
genes involved in cholesterol synthesis and fast forward drug
approval in 2015. Then early findings on transcription factors SREBP-1 and SREBP-2, respectively regulating fat synthesis and
activating all enzymes involved in the creation of a cholesterol
molecule, and experiments in animal models that led to gene
identification. Formally, proprotein convertase subtilisin/kexin
type 9 serine protease PCSK9 is actually the 9th member of its
family. But the big breakthrough in learning about its function
happened in France, where researchers found mutations in the
PCSK9 gene associated with hypercholesterolemia, suggesting
they were functional mutations.
Upon researchers realized that LDL was being affected, the
pathway was relatively straightforward. Many investigators
took approaches looking at PCSK9 expression in relation to LDL
in the liver and they’ve noticed that when PSCK9 was deleted,
the LDL receptor protein went up regulated by two-and-a-half
to threefold. The proprotein convertase subtilisin/kexin type 9
(PCSK9) enzymes is encoded in humans by the PCSK9 gene. It
plays a significant role in regulating LDL-C levels by binding to
hepatic LDL receptors and promoting their degradation, leading
to increased LDL-C levels [12,13]. These findings have led to the
development of PCSK9 inhibitors, including using monoclonal
antibodies (MoAbs), antisense oligonucleotides [14] and by RNA
interference (RNAi) mechanisms.
The most extensively studied of these PSCK9 inhibitors are the
subcutaneously administered, either fully human or humanized,
PCSK9 MoAbs. Multiple trials have been conducted with these
agents, which principally involve alirocumab, bococizumab and
evolocumab, all of which are either in late stage of development
or have been recently approved. The phase 3 programme for
alirocumab is known as ODYSSEY, whilst that for bococizumab is
called Studies of PCSK9 Inhibition and the Reduction of vascular
Events (SPIRE), with each programme containing multiple trials
prefixed by the associated programme names (e.g. ODYSSEY FH
[15], ODYSSEY LONGTERM [16], SPIRE-FH [17] and SPIRE-LDL
[18] trials). The evolocumab phase III trials are encompassed
by the Program to Reduce LDL-C and Cardiovascular Outcomes
Following Inhibition of PCSK9.
In Different Populations (PROFICIO, which includes the
completed Monoclonal Antibody Against PCSK9 to Reduce
Elevated Low density Lipoprotein Cholesterol (LDL-C) in Adults
Currently Not Receiving Drug Therapy for Easing Lipid Levels
[MENDEL]-2 [19],Goal Achievement After Utilizing an Anti-
PCSK9 Antibody in Statin Intolerant Subjects [GAUSS] [20],
Durable Effect of PCSK9 Antibody Compared with placebo Study
[DESCARTES] [21], LDL-C Assessment with PCSK9 Monoclonal
Antibody Inhibition Combined With Statin Therapy [LA-PLACE-2]
[22], Reduction of LDL-C with PCSK9 Inhibition in Heterozygous
Familial Hypercholesterolemia Disorder [RUTHERFORD]-2 [23]
and Open-Label Study of Long-Term Evaluation Against LDL-C
[OSLER] [24] trials). The development of PCSK9 MoAbs and
associated trial results to date are comprehensively summarized
elsewhere 78-90.
In summary, PCSK9 MoAbs have been shown to significantly
reduce LDL-C levels against both placebo and background lipid
therapies, with further LDL-C reductions of ~60% when used
in combination with statin compared to statin alone being
reported [13,16,22,25]. Neutralizing antibodies have not been
observed, and based on evidence to date; they appear to be well
tolerated. Two studies have specifically looked at PCSK9 MoAbs
in statin intolerant patients (the GAUSS-2 [26] and ODYSSEY
ALTERNATIVE [27] trials), with reported results indicating good
efficacy and favourable muscle symptomatology compared to
other therapies. However, injection site reactions can occur, and
studies have shown clinical outcomes when used in combination
with statin therapy.
New studies and complementary analyses of phase III
trials have consistenly shown that evolocumab and alirocumab
are highly effective in reducing LDL - C and to some extent Lp
(a). Some preliminary findings coming from exploratory and
post-hoc analyses of the longer-term safety phase III trials
and meta-analyses suggest that these mAbs can decrease
the incidence of cardiovascular events itself. Whether or not
mAbs targeting PCSK9 definitely reduce the incidence of
cardiovascular events without any safety concerns, shall be
demonstrated and documented with the results of the ongoing
cardiovascular outcome trials. Waiting the results of these
outcome trials and given the high cost of these mAbs, groups
of experts have proposed as priority groups of patients to treat
those with familial hypercholesterolemia (FH) and those with
atherosclerotic cardiovascular disease who have substantially
elevated LDL-C on maximally tolerated statin/ezetimibe therapy.
Statins remain the cornerstone of lipid management for
both primary and secondary prevention of CVD. A variety of
other lipid modifying therapies are available which can be
added to statin therapy to further reduce CV risk. Ezetimibe
is the most effective and evidence-based treatment that can
be safely added to statins, and is increasingly used in clinical
practice. Other options include fibrates, resins or nicotinic
acid. Fibrates remain widely used in lipid clinics to manage
significant hypertriglyceridaemia but their role for further CV
reduction in the absence of high triglycerides or low HDL-C has
not been proven. Bile acid sequestrants, such as the newer tablet
preparations of colesevelam, also have a role in a limited number
of patients and are effective LDL-C lowering agents if given at
sufficiently high dose, but without recent trial data to support
their use.
In contrast, nicotinic acid, despite modifying lipids, has not
been shown to reduce CV risk when added to statins and has
been shown to be associated with significant hazards. Several
large phase 3 trials of CETP inhibitors have been initiated, but
only one (REVEAL) remains ongoing after the ILLUMINATE trial
was stopped for safety concerns and the dal-OUTCOMES and ACCELERATE trials stopped for futility. A variety of novel antisense
oligonucleotides are also in development, with vaccines
offering a further potential opportunity for lipid intervention
in the future. Nowadays, PCSK9 inhibitors (evolocumab and
alirocumab recently approved) appear promising agents with
multiple trials demonstrating that these agents -in combination
with statins or monotherapy- can modify lipids substantially
with an unprecedented optimal safety profile. Several large
PCSK9 inhibitor clinical outcomes trials (ODYSSEY-OUTCOMES,
FOURIER and the SPIRE-I and II trials) are currently ongoing,
which should elucidate their place in clinical practice.
However, it remains non negotiable that keeping CVD therapy
affordable necessitates restricted use of PCSK9 antibodies to
select patient groups such as Familial Hypercholesterolemia
(FH), statin intolerance and very high CVD risk with residual
LDL burden, [1] until those currently ongoing outcome trials and
future randomized survival trials elucidate the high rank place
of these inhibitors in our cardiovascular armamentarium. In
light of this exciting era, which the medical community is facing
in lipid disorders treatment and generally in cardiovascular
disease, we should all serve a unique vision:
Educate (in details), identify (early), support and manage
patients with high and very high CV risk, not only for short and
long-term but aggressively as well. Reduction of total mortality
and CV mortality will become reality only with early, persistent,
aggressive, safe and efficient management.
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