ESC Congress 2017 In Review -- Main Edition - 31

ESC Congress 2017

PCSK9 Inhibition to Cholesterol
Written by Brian Hoyle

The successful efforts to lower levels of LDL-C over the
past 4 decades were reviewed in the PCSK9 Inhibition Cholesterol Reduction and Beyond session on 26 August
2017. The 7-year LRC trial conducted beginning in 1975
was an auspicious start, explained Steven Nissen, MD,
Cleveland Clinic, Cleveland, Ohio, USA, demonstrating
a nearly 20% reduction in LDL-C after 1 year of therapy, and reductions in the incidence of coronary heart
disease (CHD) and nonfatal myocardial infarction (MI)
[Lipid Research Clinics. JAMA. 1984].
The discovery of statins ushered in a new era of trials geared toward achieving even lower levels of LDL-C
by inhibiting hydroxymethylglutaryl-CoA reductase
using simvastatin, pravastatin, atorvastatin, and rosuvastatin. The next series of studies explored the benefits
of intensive statin therapy to achieve even lower LDL
with higher doses of atorvastatin [Cannon CP et al. N
Engl J Med. 2004; Nissen SE et al. JAMA. 2004; LaRosa
et al. N Engl J Med. 2005], simvastatin [Blazing MD,
DeLemos et al. JAMA 2004] and rosuvastatin [Nissen
SE et al. JAMA. 2006; Hsia J et al. J Am Coll Cardiol.
2011]. There is now clinical consensus that lowering LDL
with a high-intensity statin is the preferred strategy in
most high-risk patients; however, the exact strategy differs across guidelines [Stone NJ et al. Circulation. 2013;
Lloyd-Jones DM et al. J Am Coll Cardiol. 2016; Catapano
AL et al. Eur Heart J. 2016].
Subsequent to the statin trials, ezetimibe was found
to improve cardiovascular (CV) outcomes in manner that
was consistent with the degree of LDL reduction through
a nonstatin mechanism [Cannon CP et al. N Engl J Med.
2015]. These findings provided further support for concept of LDL lowering as the key determinant of CV benefit, rather than the notion that the benefit was limited
to statin therapy alone. Importantly, these findings set
the stage for alternative strategies of LDL lowering,
including those that target proprotein convertase subtilisin/kexin type 9 (PCSK9).
The role of PCSK proteins in human biology was
largely unknown 2 decades ago. The intervening brief
period of time has witnessed the unravelling of the protein's genetics and the demonstration of the functional
importance of PCSK9 in the metabolism of cholesterol.
PCSK9 is a circulating protein that binds to the receptor
for LDL [Seidah NG et al. Circ Res. 2014] and targets the
receptor for degradation in the liver, effectively blocking removal of LDL from the blood by the liver [Lambert
et al. Eur Heart J. 2016].
As described by Stephen Nicholls, MD, PhD, South
Australian Health & Medical Research Institute, Adelaide,
Australia, PCSK9 is comprised of a signal peptide, and
pro-, catalytic, and C-terminal domains. Various mutations

In Review

in these domains can produce a gain or loss of function.
Gain-of-function mutations lead to increased total cholesterol and LDL-C [Abidfadel M et. al Nat Genet. 2003].
Loss-of-function mutations are associated with lower
LDL-C levels and a reduced risk of CHD [Rashid S et al.
Proc Natl Acad Sci USA. 2005].
It has long been known that statins up-regulate
the expression of the LDL receptor, which stimulates
increased removal of LDL from the blood. More recent
evidence indicates that the binding of statin to sterol
regulatory element-binding protein 2 also up-regulates
the expression of PCSK9, which in turn increases LDL.
Thus as statin doses are escalated, the incremental
decrease in LDL is counterbalanced by increases in
PCSK9 levels, such that each doubling of statin doses
decreases the LDL by only approximately 6%. It was
hypothesised that the addition of a PCSK9 inhibitor to
statin therapy should have the potential to dramatically
lower LDL.
This hypothesis has been borne out in studies of
monoclonal antibodies targeted against PCSK9, including evolocumab [Sabatine MS et al. N Engl J Med. 2015],
alirocumab [Robinson JG et al. N Engl J Med. 2015], and
bococizumab [Ridker P et al. N Engl J Med. 2017], each
significantly and substantially reduced LDL-C by 40-70%
when added to background statin therapy. PCSK9 inhibitors also reduced levels of lipoprotein(a), which has been
implicated in CV disease. Dr Nicholls and colleagues have
proposed that physiological concentrations of PCSK9
enhance the production of lipoprotein(a) and that inhibition of PCSK9 will reduce lipoprotein(a) levels.
Evolocumab has been shown to result in a significantly lower atheroma volume in the GLAGOV study
[Nicholls S et al. JAMA. 2016]. Notably, in the FOURIER
trial of 27,564 high-risk patients with stable atherosclerotic disease, evolocumab significantly reduced major
adverse cardiac events (CV death, MI, or stroke) by 20%
(P < .001) [Sabatine MS et al. N Engl J Med. 2017]. There
was also a significant reduction in CV events in SPIRE 2
with bococizumab in patients at higher-risk; however, the
SPIRE trials were terminated early due to development
of neutralizing antibodies to this humanised murine
antibody. The outcomes trial with alirocumab, ODYSSEY
Outcomes, is ongoing to assess for cardiovascular benefit of LDL reduction with this agent [NCT01663402].
Therapies to reduce LDL-C and CV events must be
safe in both the short and long term. PCSK9 directed
therapy has been in use for a relatively short period of
time (up to 4 years) and therefore longer-term safety
data are needed, according to J. Woulter Jukema, MD,
PhD, Leiden University Medical Centre, Leiden, The
Netherlands. In the FOURIER trial, there were no safety
concerns identified in the main trial (Table 1) as well as in
a cognitive study known as EBBINGHAUS that was
embedded within FOURIER [Giugliano RP et al. N Engl J

Official Peer-Reviewed Highlights From ESC Congress 2017

Table of Contents for the Digital Edition of ESC Congress 2017 In Review -- Main Edition