PCSK9 – Inhibitors what do they do and do they work? –
Oliver McConell, Ashish Dhawan
Hyperlipidaemia is a well-established risk factor for developing cardiovascular disease. Multiple randomized controlled trials have shown that lowering LDL levels correlates with reduced cardiovascular events.
Currently statins are the cornerstone of treatment for lipid lowering but some patients continue to have events on maximal doses and others develop side effects that limit statin use. PCSK9 inhibitors are leading a new era of lipid lowering therapies.
What is PCSK9?
Proprotein convertase subtilisin / kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene on chromosome 1.
This protein plays a major regulatory role in cholesterol homeostasis, mainly by reducing LDL receptor (LDLR) levels on the plasma membrane. Reduced LDLR levels results in decreased metabolism of LDL-particles, which can lead to hypercholesterolemia.
Are there any other effects of PCSK9?
PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis.(1) It is well known that PCSK9 is pro-atherosclerotic in its regulatory effects of lipids.
In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity, (2) regulation of re-absorption of sodium in the kidney which is relevant in hypertension. (3) PCSK9 is also thought to be involved in both bacterial and viral infections and sepsis. (4) In the brain the role of PCSK9 is still controversial and may be either pro-apoptotic or protective in the development of the nervous system. (5)
How do PCSK9 inhibitors work?
LDL-particles are removed from the blood when they bind to LDLR on the surface of cells.
When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.(6) If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.(7)
Hence inhibition of PCSK9 will allow LDLR to be recycled to the cell surface and continue to remove LDL cholesterol.
PCSK9 inhibitors are monocloncal antibodies that are given by subcutaenous injection every 2 weeks. They are delivered to patients’ homes directly and they self administer the injections with regular follow up and monitoring of lipids.
The ODYSSEY LONG TERM trial (9) was published in the New England Journal of Medicine in April 2015 . The trial was designed to obtain longer-term data on safety and reduction in LDL cholesterol levels. It also looked at post hoc analysis of cardiovascular events. The PCSK9 inhibitor in this series was alirocumab. The trial assigned 2341 high-risk patients to either the PCSK9 inhibitor alirocumab or placebo. As compared with placebo, alirocumab reduced LDL cholesterol levels by 62% at 24 weeks, with a consistent reduction over a period of 78 weeks of treatment. In a post hoc analysis, there was evidence of a reduction in cardiovascular events with alirocumab.
The national institute for clinical excellence (NICE) have put strict controls on the criteria for prescribing of PCSK9 inhibitors in view of their high cost. NICE have estimated annual cost of treatment per patient is £4,383. The have created the following treatment recommendation:
Real world experience of PCSK9 inhibitors Our experience of PCSK9 inhibitors was with in a district general hospital which runs a regional lipid clinic for challenging hyperlipidaemia and FH patients. This serves a population of around 1,000,000 in the north west of England. Patients who met the criteria for PCSK 9 inhibitors were prescribed alirocumab.
In total 24 patients were successfully started on alirocumab over a 12 month period. The average age of patients was 57 . 54% of patients were male. 30% of the FH patients had previously had a cardiovascular event at initiation of treatment. All patients were on the maximum tolerated dose of lipid lowering therapy (LLT). Of those started on alirocumab, 63% of were intolerant to high dose statins with 46% being intolerant to all statins.
Three people discontinued the drug due to intolerance. However, there was an average 49% reduction in low density lipoprotein (LDL) cholesterol levels from baseline on maximal tolerated dose of LLT . In our experience, the reduction in LDL seen in a real world setting with alirocumab mirrored that of the reductions seen in the clinical trials. It proved to be a welltolerated, effective method of reducing LDL cholesterol alongside maximum tolerated doses of lipid lowering therapies.