The UK for
instance,
requires LDL-C
levels >155mg/
dl (4.0mmol/l)
in those who are
at high risk, and
levels >135mg/
dl (3.5mmol/l)
in those at
very high risk
to justify the
use of a PCSK9
inhibitor for
secondary
prevention
Although PCSK9 inhibitors have shown dramatic
reductions in LDL-C, 16,17 there is a lack of
convincing evidence that this would translate into
a mortality benefit, as detected in the past
with fibrates, torcetrapib and extended-release
niacin–laropiprant. 19
Furthermore, those most likely to benefit
from PCSK9 inhibitors are those with familial
hypercholesterolaemia. Heterozygous familial
hypercholesterolaemia has a prevalence of 1 in
500 in Europe. 20 However, in those with the most
rare and the most severe homozygous forms of
familial hypercholesterolaemia, LDL receptors are
either defective or absent, and PCSK9 inhibitors
would provide very limited benefit over existing
therapies. 21
Both evolocumab and alirocumab would
require life-long injections. 16 Neurocognitive
adverse events have been described with PCSK9
inhibitors but remain uncharacterised and
longer-term follow-up period would be crucial
in this context to assess their significance. 15
Finally, the cost per treatment of PCSK9
inhibitors is currently prohibitively high and
would be a major obstacle that would affect
their adoption in the clinical practice and reduce
long-term adherence. The current cost of PCSK9
inhibitors are 100-fold more expensive than
generic statins. 19,22 A review of the major economic
simulation models found that the projected
cost-effectiveness of PCSK9 inhibitors did not
meet the generally accepted benchmarks for good
value in the US, but their value would be improved
if their prices were reduced substantially. 22
Therefore, more discussion between the health
policy-makers and the pharmaceutical companies
are required in this regard.
Future directions
One of the ways to get circumvent the financial
constraints surrounding the use of PCSK9
inhibitors would be to restrict their use to those
at highest risk, with documented atherosclerotic
CVD and with sub-optimal LDL-C levels despite
high doses of statin or in those who are truly
intolerant of statins. The National Institute
for Health and Care Excellence in the UK for
instance, requires LDL-C levels >155 mg/dl
(4.0mmol/l) in those who are at high risk, and
levels >135mg/dl (3.5mmol/l) in those at very
high risk to justify the use of a PCSK9 inhibitor
for secondary prevention but it is currently not
indicated for primary prevention in those with
primary non-familial hypercholesterolaemia or
mixed dyslipidaemia. 23,24 The indication for its
use is bound to evolve in the next few years
pending the availability of longer-term follow-up
data with hard endpoints and a reduction in
its cost.
Conclusions
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. It is not yet well
established whether their potent effects on
reducing LDL-C will translate directly into lower
mortality and further larger studies with longer
follow-up periods are warranted before it can be
considered cost-effective.
7
HHE 2018 | hospitalhealthcare.com
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