Page 478 - Read Online

Agdamag et al. Vessel Plus 2020;4:42 I http://dx.doi.org/10.20517/2574-1209.2020.60 Page 3 of 9

PCSK9 inhibitors. Two subcutaneous products, evolucumab (Amgen Inc, Thousand Oaks, CA, USA) and
alirocumab (Sanofi SA, Paris, France; and Regeneron Pharmaceutical Inc, Eastview, New York, USA), are
currently approved by the FDA, both of which are human monoclonal antibodies with identical mechanism
of action. Three landmark clinical trials have evaluated these medications with their results transforming
the landscape of lipid management. OSLER, ODYSSEY, and FOURIER have been recently published. These
were randomized, controlled, outcome trials that explored the impact of evolocumab or alirocumab on
serum LDL-C reduction, risk of cardiovascular events and safety outcomes [18-20] . All enrolled patients were
at high risk or had documented ASCVD when entering the clinical studies. PCSK9 inhibitors were used
on top of moderate or high-intensity background statin therapy in the treatment groups. The three trials
confirmed a sustained, approximately 60% reduction in serum LDL-C level when compared to placebo.
This was accompanied by a significant reduction in adverse clinical outcomes, including death, unstable
angina, myocardial infarction and ischemic stroke. Importantly, progressively lower serum LDL-C levels,
[21]
even below previously reported target values, were not associated with worse outcomes . The drugs are
well-tolerated in general with injection-site reactions, mild influenza-like illness and self-limiting myalgias
[22]
as the most frequently reported side effects in real-world experience . However, they are quite expensive.
Their role may be of greater importance in patients with familiar hypercholesterolemia and in post-heart
transplant population where long-term treatment is necessary.

In addition to the monoclonal antibodies already in clinical practice, small interfering RNAs (siRNAs)
are also under investigation with the aim to reduce circulating PCSK9 levels. SiRNAs interfere with the
expression of specific genes by promoting mRNA degradation prior to translation. Inclisiran is a long-
acting siRNA that targets hepatic PCSK9 synthesis and has been shown to significantly reduce circulating
LCL-C levels. It has the distinct advantage of twice per year dosing and acting at the intracellular level
[23]
of hepatocytes . It is currently awaiting FDA approval that is expected by the end of 2020. Vaccination
aiming to develop PCSK9-specific antibodies are also under investigation. DSPE-PEG-maleimide lipid
(L-IFPT) adsorbed to Alhydrogel® (L-IFPTA+) administration has shown to induce a high IgG antibody
[24]
response, specific against the PCSK9 peptide in hypercholesterolemic mice . This was paralleled by a 42%
reduction in circulating LDL-C levels. This approach could provide safe and long lasting PCSK9 inhibition,
as well as decrease the cost and frequency of administration [24,25] .

CURRENT GUIDELINES ON THE USE OF PCSK9 INHIBITORS
The 2018 ACC/AHA/NLA (American College of Cardiology/American Heart Association/National Lipid
Association) cholesterol guidelines for clinical practice utilize the ASCVD risk calculator to determine
if a patient would benefit from interventions reducing LDL-C levels. Two large meta-analyses have
confirmed that ASCVD risk declines progressively as serum LDL-C is lowered using statin therapy [26,27] .
Guidelines now define cholesterol-lowering goals in terms of absolute LDL-C level and percentage LDL-C
reduction. The calculated 10-year ASCVD risk is classified into “low risk” < 5%, “borderline risk” 5%-
[4]
7.5%, “intermediate risk” 7.5%-20% and “high risk” > 20% groups , which determines the recommended
intensity of statin therapy (low, moderate, or high). The guidelines also identify a group of patients who
are thought to benefit from additional lower levels of LDL-C, with target levels below 70 mg/dL. At times,
this goal may only be achieved when prescribing a high-intensity statin combined with a medication
from a different drug class. Ezetimibe is currently the first line adjuvant agent, and PCSK9 inhibitors are
[4]
considered second line adjunctive agents . Current guidelines also identify additional groups of patients
who should be initiated on a PCSK9 inhibitor given their high ASCVD risk. These include individuals with
heterozygous familial hypercholesterolemia with an LDL-C of 100 mg/dL or higher, patients with LDL-C
level exceeding 220 md/dL, and persistently elevated serum LDL-C above 130 md/dL despite a combination
[4]
of high-intensity statin and ezetimibe .