PCSK9 Inhibition in Atherosclerotic Cardiovascular Disease

Abstract

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a novel class of hypolipidemic drugs, providing an additional therapeutic option over conventional hypolipidemic treatments. Given the constantly lowering recommended LDL-C goals, low goal achievement rate and low compliance with treatment, new hypolipidemic drug classes may substantially contribute to residual risk reduction for atherosclerotic cardiovascular disease (ASCVD). This review aims to summarize contemporary evidence on the clinical role of PCSK9i in ASCVD prevention. PubMed and MEDLINE databases were searched for keywords in studies on PCSK9i and ASCVD. Approved PCSK9i are the monoclonal antibodies (Mabs), evolocumab and alirocumab, targeting PCSK9, and inclisiran, a small interfering RNA inhibiting PSCK9 synthesis. Overall, PCSK9i effectively reduced LDL-C and other atherogenic lipoproteins, including apolipoprotein B and lipoprotein(a) primarily. PSCK9i Mabs improved imaging markers reflecting coronary atherosclerotic plaque vulnerability and reduced ASCVD events in high-risk patients after short-term treatment ( < 3 years follow-up). They are currently indicated as a third-line treatment for secondary prevention and primary prevention in patients with familial hypercholesterolemia at high risk of not achieving their LDL-C goals. Patients with higher baseline ASCVD risk receive greater benefits from PCSK9i. Recent evidence suggests that evolocumab was effective and safe after long-term treatment. Ongoing trials investigate new therapeutic indications for PCSK9i while their cost-effectiveness is still being considered. PCSK9i is a novel hypolipidemic drug class currently indicated for reducing residual risk in secondary ASCVD prevention and high-risk patients.

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“…When PCSK9 concentration is high, PCSK9 will enhance the degradation of LDL-R in acidic lysosomes and then increased serum LDL concentration. In the absence of PCSK9, LDL-R exists at the cell surface and delivery of LDL-C particles to degradation in acidic endosomes, and then, LDL-R recycled back to the cell surface [ 40 – 42 ].…”

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“…2 PCSK9 inhibitors are highly effective at lowering LDL levels and are generally well tolerated. [2][3][4][5][6] Fibrates and niacin are useful in certain patients with severe hypertriglyceridemia. 2 Fibrates are generally well tolerated…”