PCSK9 inhibitors and LDL-C levels
The monoclonal antibodies evolocumab and
alirocumab directed at PCSK9 were the first class
to be approved. Both can be administered by
subcutaneous injection every two to four weeks.
They have shown impressive reduction in LDL-C
levels when compared with placebo, whether
used alone or added to standard therapy in two
large randomised controlled trials (RCTs). 12,13
The average LDL-C levels fell by approximately
60% from around 120mg/l (3.15mmol/l) to
around 50mg/l (1.3mmol/l). Of note, most trial
participants were already taking statins or
ezetimibe. adequately powered for hard clinical endpoints.
However, when combined in meta-analyses, there
was evidence that PCSK9 inhibitors reduced the
incidence of all-cause mortality. 14,15
The FOURIER trial 16 was powered to assess the
impact of evolocumab on hard clinical outcomes.
This study recruited more than 27,000 patients
with atherosclerotic CVD and LDL-C >70mg/
dl despite being on a statin (with or without
ezetimibe) therapy. They were randomised to
evolocumab (either 140mg every two weeks or
420mg monthly) or matching placebo. LDL-C was
significantly reduced from a median of 92mg/dl to
30mg/dl within a month. After a median follow-up
of 2.2 years, the primary composite endpoint
of cardiovascular death, myocardial infarctio n,
stroke, hospitalisation for unstable angina or
coronary revascularisation was significantly lower
with evolocumab when compared with placebo
(9.8% versus 11.3%; hazard ratio 0.85; 95% CI
[0.79–0.92]). This was mainly driven by
a reduction in myocardial infarction, stroke, and
coronary revascularisation. Of note, the incidence
of neurocognitive events and new-onset diabetes
were similar between the two treatment arms.
Only injection site reactions were more frequent
with evolocumab (2.1% versus 1.6%).
An updated meta-analysis 17 of 35 RCTs (45,539
patients) including the FOURIER trial confirmed
that treatment with a PCSK9 inhibitor is well-
tolerated and improved cardiovascular outcomes.
Although there was no overall benefit in all-cause
or cardiovascular mortality, meta-regression
analysis showed a significant association
between higher baseline LDL-C and benefit in
all-cause mortality (p = 0.038). This implies that
those with higher baseline LDL-C may have
a mortality benefit if treated with a PCSK9
inhibitor. 17 This finding is hypothesis generating
and warrants further investigation. The ODYSSEY
OUTCOMES (NCT01663402) study is
investigating the benefit of alirocumab on clinical
outcomes in patients with recent acute coronary
syndrome. This study has completed the recruited
of 18,600 patients and its findings are eagerly
awaited.
Not all reductions in LDL-C by PCSK9
inhibitors have translated to an improvement in
clinical outcome. Bococizumab is a humanised
monoclonal antibody against PCSK9 and was
recently announced in the joint SPIRE-1 and
SPIRE-2 trials. 18 Around 27,000 patients with
variable baseline lipid-lowering therapy and
atherosclerotic CVD status were enrolled.
After 14 weeks, LDL-C was 59% lower in the
bococizumab arm. However, after a median
follow-up of seven months, there was no
significant difference in the composite endpoint
of myocardial infarction, stroke, hospitalisation
for unstable angina requiring urgent
revascularisation, or cardiovascular death. This
study was terminated early due to bococizumab
showing a propensity to develop antidrug
antibodies and this explains the short follow-up
duration. 18 For this reason, bococizumab is not
licensed for clinical use.
PCSK9 inhibitors and clinical outcomes
Numerous Phase III RCTs 14,15 have investigated
the safety and efficacy of evolocumab and
alirocumab in reducing LDL-C but none were Challenges facing PCSK9 inhibitors
Despite their initial promise, there are numerous
challenges facing the widespread adoption
of PCSK9 inhibitors in the clinical setting.
carriers of certain PCSK9 polymorphisms had
significantly lower rates of atherosclerotic CVD. 11
These promising findings led to the development
of several classes of PCSK9 inhibitors to target the
PCSK9 pathway in order to reduce LDL-C.
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