Address for
Correspondence: Prof. Dr. Johnson Francis, Senior
Consultant Cardiologist, Baby Memorial Hospital, Kozhikode,
Kerala, India, PIN 673017. Email: pulikkottil2002@hotmail.com
Keywords: PCSK9 Inhibitors, Dyslipidemia, Evolocumab,
Alirocumab
Dyslipidemia is a well known risk factor for
cardiovascular disease. Till now statins were the sheet anchor
of therapy for dyslipidemia. But there are a few patients who
are intolerant to statins and some who develop cardiovascular
disease in spite of maximally tolerated dose of statins. Still
there are some others like those with familial
hypercholesterolemia who do not achieve adequate reduction of
cholesterol levels with statins alone or in combination with
ezetimibe. Now we have a new group of medications - proprotein
convertase subtilsin-kexin type 9 (PCSK9) inhibitors, to cater
to these group of patients.
Two drugs belonging to this novel class of PCSK9 inhibitors
have been approved by the United States Food and Drug
Administration in the last few years: Evolocumab and
Alirocumab. These are monoclonal antibodies targeting
PCSK9, which is a hepatic protease involved in the
internalization of LDL (Low Density Lipoprotein) cholesterol
receptors into the lysozymes. Blockage of PCSK9 prevents the
destruction of LDL receptors by lysozymes and hence can
achieve LDL-C reduction 50-60% above that achievable by statin
therapy [1].
Over the years, it has been noted that patients with
genetically lower LDL have correspondingly better
cardiovascular event reductions than in those who have
pharmacologically lower LDL. This is possibly due to lifetime
lower LDL levels. PCKS9 mutations (rs11591147 T allele)
producing lower levels of LDL have been shown to have markedly
lower cardiovascular event rates [2].
Further Cardiovascular Outcomes Research With PCSK9 Inhibition
in Subjects With Elevated Risk (FOURIER) trial [3], evaluated
27,564 patients with atherosclerotic cardiovascular disease
and LDL cholesterol levels of 70 mg/dl or more who were
receiving statin therapy. They were randomised to
evolucumab (either 140 mg every 2 weeks or 420 mg
monthly) or matching placebo as subcutaneous injections.
Median follow up period was 2.2 years and the primary efficary
end point was a composite of cardiovascular death, myocardial
infarction, stroke, hospitalization for unstable angina, or
coronary revascularization. LDL cholesterol levels were
reduced to a median level of 30 mg/dl. There were no
significant increase in the adverse events including new onset
diabetes mellitus and neurocognitive events. But
injection-site site reactions were more common with
evolocumab. Evolocumab reduced primary endpoint by 18% [4]. It
may be noted that all these patients were on statin therapy,
with 69% of them taking high-intensity statin therapy.
An analysis of FOURIER trial investigated the efficacy and
safety of evolocumab in patients with peripheral artery
disease (PAD) as well as the effect on major adverse limb
events [5]. Around thirteen percent of patients (3642 out of
27564) had PAD, of which 1505 had no prior myocardial
infarction or stroke. As these patients were at higher risk,
they had larger absolute reductions of primary end point (3.5%
with PAD, 1.6% without PAD). Evolocumab reduced the risk of
major adverse limb events in all patients (HR, 0.58; P=0.0093)
and there was consistent relationship with lower LDL levels.
Long-term Safety and Tolerability of Alirocumab in High
Cardiovascular Risk Patients with Hypercholesterolemia Not
Adequately Controlled with Their Lipid Modifying Therapy
(ODYSSEY LONG TERM) involved 2341 patients at high risk of
cardiovascular events and LDL cholesterol of 70 mg/dl or more
while on maximum tolerated dose of statins [6]. They were
randomised in a 2:1 ratio to receive either alirocumab (150
mg) or placebo as a 1-ml subcutaneous injection every 2 weeks
for 78 weeks. Though higher rates of injection-site reactions
were noted in the active treatment group, they had significant
reductions of LDL cholesterol levels (mean reduction of 62
percentage points, P<0.001). A post hoc analysis also
documented lower rates of cardiovascular events (1.7%
vs. 3.3%; nominal P=0.02). Reduction in lipoprotein (a) was 26
percentage points in this trial.
An often raised question has been regarding the safety of
profound reductions in LDL-C levels. Reductions to levels
below 25 mg/dl noted commonly in trials of PCSK9 inhibitors
have been accompanied by low rates of atherosclerotic coronary
events, suggesting that there may be no lower limit for LDL-C
reduction [7].
Important limitation of PCSK9 inhibitors is the cost of
therapy. Moreover no benefit on cardiovascular or all-cause
mortality has been demonstrated so far in the relatively
shorter duration of follow up compared to statins. But they
are useful in achieving good reductions of LDL cholesterol in
those with atherosclerotic cardiovascular disease not at goal
despite maximally tolerated statin therapy. They do have a
role in familial heterozygous and homozygous
hypercholesterolemia as well.
References
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Leng Y, Chen R. What is the impact of PCSK9 rs505151 and
rs11591147 polymorphisms on serum lipids level and
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Jun 12;16(1):111. doi: 10.1186/s12944-017-0506-6.
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