PCSK9 Inhibitors

PCSK9 inhibitors block proprotein convertase subtilisin/kexin type 9, a protein that directs LDL receptors for lysosomal degradation. Blocking it increases LDL receptor recycling and lowers LDL cholesterol by 50% to 60% on top of statins, reducing cardiovascular events. They are injectable and expensive, so they are reserved for very high risk patients and familial hypercholesterolaemia.

Members. Monoclonal antibodies: alirocumab and evolocumab. Small interfering RNA: inclisiran, which reduces hepatic production of PCSK9.

Mechanism. Antibodies bind circulating PCSK9. Inclisiran silences PCSK9 messenger RNA in hepatocytes, with effect lasting months.

Pharmacokinetics. Subcutaneous injection, with peak effect of antibodies at 1 to 2 weeks and half-lives of days. Inclisiran is cleared slowly with a duration of action of 6 months. None is cleared by the liver enzymes or kidney in a way that causes dose adjustment, so interactions are few.

• Alirocumab: every 2 weeks or monthly.
• Evolocumab: every 2 weeks or monthly; also licensed in homozygous familial hypercholesterolaemia.
• Inclisiran: twice-yearly maintenance, given by a health professional, which improves adherence.

• Indication: established atherosclerotic disease or heterozygous familial hypercholesterolaemia with LDL cholesterol over target despite maximum tolerated statin and ezetimibe; or statin intolerance.
• Alirocumab: 75 mg subcutaneously every 2 weeks (increase to 150 mg if LDL reduction is inadequate), or 300 mg every 4 weeks.
• Evolocumab: 140 mg subcutaneously every 2 weeks or 420 mg monthly. In homozygous familial hypercholesterolaemia 420 mg monthly (every 2 weeks with apheresis).
• Inclisiran: 284 mg subcutaneously at day 0, at 3 months, then every 6 months.
• Timing: can start in hospital after acute coronary syndrome when LDL cholesterol is well over target.
• Selection: add to statin and ezetimibe. Check cost, supply, cold storage and patient or nurse injection ability before starting.

Contraindications. Hypersensitivity to the drug. Pregnancy and breastfeeding are avoided because of limited data.

Adverse effects. Injection site reactions, nasopharyngitis and upper respiratory symptoms, influenza-like illness, myalgia, and rarely allergic reactions. Neutralising antibodies are uncommon. No increase in cognitive events, diabetes or muscle disease has been confirmed.

Interactions. Few. They do not alter statin levels. LDL apheresis lowers drug levels.

Storage. Antibodies are stored refrigerated (2 to 8 degrees Celsius) and can stay at room temperature for up to 30 days, which limits use where cold-chain access is poor. Inclisiran is stored at room temperature.

Monitoring. LDL cholesterol 4 to 12 weeks after starting, then yearly. Adherence and injection technique. Liver enzymes at baseline.

Referral and escalation. Specialist or lipid clinic review for familial hypercholesterolaemia, LDL cholesterol that stays high, and children.

Special groups. Kidney or hepatic impairment: no dose change in mild to moderate disease. Older adults: no dose change. Children: evolocumab is licensed in adolescents with familial hypercholesterolaemia in some regions. Region: cost and availability are the main limits to use.