PCSK9 (proprotein convertase subtilisin/kexin type 9) is a liver-derived regulator of LDL-receptor recycling. Blocking its activity — or reducing its production — lowers LDL cholesterol by about 50–60% on top of statins. In Australia these therapies are used mainly for high-risk patients with established atherosclerotic cardiovascular disease or familial hypercholesterolaemia who remain above LDL-C targets despite maximally tolerated lipid-lowering therapy.
- PCSK9 degrades the hepatic LDL receptor; lowering its activity increases receptor recycling and accelerates LDL clearance.
- Evolocumab, a monoclonal antibody, lowers LDL-C by about 50–60%, with further reductions in ApoB (~45–55%), Lp(a) (~20–30%) and triglycerides.
- The FOURIER trial showed a 15% reduction in major cardiovascular events; FOURIER-OLE confirmed sustained benefit and safety over up to 8.4 years.
- VESALIUS-CV (2025) extended evolocumab’s benefit to high-risk patients without a prior heart attack or stroke — a 25% reduction in major coronary and stroke events.
- Inclisiran is a twice-yearly siRNA that reduces hepatic PCSK9 production. It lowers LDL-C substantially, but definitive cardiovascular outcome data are still awaited.
- In Australia, evolocumab and inclisiran are available on the PBS under Authority criteria for selected high-risk patients; eligibility wording is revised periodically.
What are PCSK9 inhibitors?
PCSK9 is a circulating protein, made mainly in the liver, that controls how much LDL cholesterol the liver can clear from the blood. PCSK9 inhibitors are a class of drugs that reduce its effect — either by binding the protein in the circulation (the antibody evolocumab) or by suppressing its production in the liver (the siRNA inclisiran). Both result in more LDL receptors clearing more LDL, and a large fall in LDL cholesterol on top of statins. The class has become one of the most important advances in preventive cardiology since the statins.
How PCSK9 controls LDL receptors
LDL receptors on the liver-cell surface capture LDL particles and draw them into the cell, where the particle is broken down. The receptor is then recycled back to the surface to capture more LDL — each receptor can be reused up to about 150 times (Fig 1).
PCSK9 disrupts this cycle. It binds the LDL receptor as it is taken into the cell; the bound receptor is then destroyed instead of recycled (Fig 2). Fewer receptors return to the surface, so less LDL is cleared and blood LDL-C rises.
Why PCSK9 became a drug target
PCSK9 was identified in 2003. In the same year, gain-of-function mutations were linked to familial hypercholesterolaemia; soon after, loss-of-function variants were shown to produce the opposite pattern — lifelong lower LDL-C and markedly lower coronary risk, with no apparent harm. This natural experiment is what made PCSK9 such an attractive target.
Higher LDL, higher risk
More active PCSK9 → more receptor degradation → fewer receptors → higher LDL cholesterol (an inherited form of FH).
Lower LDL, lower risk
Less active PCSK9 → lifelong low LDL-C and markedly reduced coronary risk, with no apparent harm.
Evolocumab
Evolocumab is a monoclonal antibody that binds circulating PCSK9 and blocks its activity (Fig 3). With PCSK9 neutralised, more LDL receptors are recycled to the cell surface, increasing LDL clearance. The effect is large and largely independent of background therapy: LDL-C falls by about 50–60% on top of statins, with reductions of approximately 45–55% in apolipoprotein B, 20–30% in lipoprotein(a), and a modest fall in triglycerides. This makes it especially useful when statins alone are insufficient or are not tolerated.
Evolocumab is given by subcutaneous injection: 140 mg every 2 weeks, or 420 mg once monthly. Its long duration of action allows this convenient dosing. A second antibody, alirocumab, is used overseas but is not currently marketed in Australia.
Inclisiran: related but different
A second approach lowers PCSK9 at its source. Inclisiran is a small interfering RNA (siRNA) that degrades PCSK9 messenger RNA inside the liver cell, suppressing production of the protein rather than mopping it up in the circulation. It is given subcutaneously on day 1, again at 3 months, then only twice yearly — an adherence advantage. LDL-C reductions are broadly comparable (about 50%), though definitive cardiovascular outcome data are still awaited. A full account is in the dedicated inclisiran article.
Outcome evidence
The clinical question is not just whether LDL-C falls, but whether events fall with it.
27,564 patients with ASCVD
Stable ASCVD on a statin, LDL-C ≥1.8 mmol/L. LDL-C fell 59%. Over a median 2.2 years: a 15% reduction in the primary composite, and a 20% reduction in the key secondary composite of cardiovascular death, MI or stroke.
12,257 patients, no prior MI or stroke
High risk from atherosclerosis or diabetes but no previous event, on optimised lipid-lowering therapy. LDL-C fell ~55%. Over a median ~4.6 years: a 25% reduction in 3-point MACE (CHD death, MI, ischaemic stroke) and 19% in 4-point MACE; all-cause mortality 7.9% vs 9.7%.
LDL-C efficacy only
Confirmed durable ~50% LDL-C lowering in FH and ASCVD. Cardiovascular outcomes are awaited from ORION-4 and VICTORION-2P (ongoing).
Evolocumab reduces non-fatal atherosclerotic events — myocardial infarction, ischaemic stroke and coronary revascularisation — both in patients with a prior event (FOURIER) and, more recently, in high-risk patients without a prior MI or stroke (VESALIUS-CV). The absolute benefit is greatest in the highest-risk patients, who have the most events to prevent.
Safety
Safety was a major focus of FOURIER, particularly because many candidates cannot tolerate statins. Aside from a small excess of injection-site reactions, there was no increase in muscle symptoms, liver enzyme elevation, new diabetes, cataract or adverse cognitive effects. The EBBINGHAUS sub-study specifically measured cognition and found no difference between evolocumab and placebo.
The open-label extension followed patients for a median of 5 years (maximum evolocumab exposure 8.4 years), with very low LDL-C sustained and no new safety signals. These data are reassuring, although clinical follow-up beyond the trial durations is inherently limited.
Who may benefit?
PCSK9 inhibitors are reserved for high-risk patients who remain off-target despite optimised conventional therapy. In practice this means a patient with established atherosclerotic cardiovascular disease — prior MI, coronary stenting or bypass, ischaemic stroke or peripheral arterial disease — or imaging evidence of significant atherosclerosis where treatment escalation is clinically justified, or familial hypercholesterolaemia, who has maximised tolerated statin therapy. Ezetimibe and bempedoic acid should be considered first or alongside. If LDL-C remains above target after these steps, a PCSK9 inhibitor is indicated (Fig 4). A structured stepwise approach helps in severe hyperlipidaemia. VESALIUS-CV now supports treating high-risk patients before a first event — those with atherosclerosis or high-risk diabetes still above target — and evolocumab’s regulatory indication has broadened accordingly; in Australia, subsidised access continues to follow PBS criteria, which can lag the evidence.
Access in Australia
In Australia, evolocumab and inclisiran are available on the PBS under Authority criteria for selected patients with familial hypercholesterolaemia, or with hypercholesterolaemia and high cardiovascular risk, who remain above LDL-C targets despite maximally tolerated lipid-lowering therapy. Eligibility wording and thresholds are revised periodically — confirm current criteria on the PBS schedule.
Frequently asked questions
What is the difference between a PCSK9 antibody and inclisiran?
Both lower PCSK9, but in different ways. Evolocumab is a monoclonal antibody that binds and neutralises PCSK9 already in the bloodstream, and is injected fortnightly or monthly. Inclisiran is a small interfering RNA that stops the liver from making PCSK9 in the first place, and is injected only twice a year after two starting doses.
How much do PCSK9 inhibitors lower cholesterol?
Evolocumab lowers LDL cholesterol by about 50–60% on top of a statin, with further reductions in ApoB, lipoprotein(a) and triglycerides. Inclisiran achieves broadly similar LDL-C lowering of around 50%.
Are PCSK9 inhibitors safe long term?
Yes. Aside from a small excess of injection-site reactions, the trials showed no increase in muscle symptoms, diabetes, liver enzyme rise, cataract or cognitive effects. The FOURIER open-label extension supported safety over up to 8.4 years, even at very low LDL-C levels.
How are they given?
By subcutaneous injection. Evolocumab is dosed every 2 weeks or monthly; inclisiran is given at day 1, at 3 months, then twice a year.
Do PCSK9 inhibitors replace statins?
No. Statins remain first-line. PCSK9 inhibitors are added when a high-risk patient remains above target despite a maximally tolerated statin and other non-statin therapy, or when statins genuinely cannot be tolerated.
References and further reading
Clinical references
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease (FOURIER). N Engl J Med. 2017.
- Bohula EA, Giugliano RP, Leiter LA, et al. Evolocumab in patients without a previous myocardial infarction or stroke (VESALIUS-CV). N Engl J Med. 2025.
- O’Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-term evolocumab in patients with established ASCVD (FOURIER-OLE). Circulation. 2022.
- Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab (EBBINGHAUS). N Engl J Med. 2017.
- Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol (ORION-10 and ORION-11). N Engl J Med. 2020.
- Sabatine MS. PCSK9 inhibitors: what we know, what we should have understood, and what is to come. Eur Heart J. 2019.
Related reading on this site
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