Intervention

PCSK9 Inhibitors

Last updated Sat May 30 2026 00:00:00 GMT+0000 (Coordinated Universal Time)

RCT evidence— FOURIER + ODYSSEY OUTCOMES

What they are

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a circulating protein that binds LDL receptors and targets them for lysosomal degradation. Inhibiting PCSK9 increases LDL receptor density on hepatocytes, dramatically lowering plasma LDL.

Approved agents

Evolocumab (Repatha): fully human monoclonal antibody.
Alirocumab (Praluent): fully human monoclonal antibody.
Inclisiran (Leqvio): siRNA targeting PCSK9 mRNA — see Inclisiran (twice-yearly dosing).

Outcomes evidence

FOURIER (evolocumab, 2017): 15% relative reduction in major cardiovascular events over 2.2 years in established ASCVD.
ODYSSEY OUTCOMES (alirocumab, 2018): 15% relative reduction post-ACS.
FOURIER-OLE (open-label extension): benefit grew with longer exposure.
No safety floor identified down to LDL ~30 mg/dL; no cognitive, cataract, or haemorrhagic-stroke signals.

Indications

Established ASCVD on max-tolerated statin + ezetimibe with LDL still above target.
Familial hypercholesterolaemia.
Statin intolerance (with documented inability to tolerate multiple statins).
Very high Lp(a) (lowers Lp(a) ~25% as a bonus).

References

Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease (FOURIER). N. Engl. J. Med. 376, 1713–1722 (2017).