Physicians' Academy for Cardiovascular Education

PCSK9-antibodies do not significantly affect balance cholesterol synthesis and absorption

The Interrelations between PCSK9-Metabolism and Cholesterol Synthesis and Absorption

Literature - Silbernagel G, Steiner LK, Hollstein T, et al. - J Lipid Res 2018; published online ahead of print

Introduction and methods

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-antibodies are known to reduce LDL-c, and decrease the risk of cardiovascular events, but there is limited evidence regarding the interrelations between PCSK9 metabolism, cholesterol synthesis, and cholesterol absorption [1]. In the present study, the impact of treatment with PCSK9-antibodies on cholesterol synthesis and absorption was assessed, in the context of an observational study.

For this purpose, the circulating cholesterol precursor lathosterol was measured to estimate cholesterol synthesis, and the plant sterols campesterol and sitosterol were measured to estimate cholesterol absorption [2,3], in 245 patients aged ≥ 18 years, with hypercholesterolemia, who routinely received PCSK9-antibodies (alirocumab 75 or 150 mg sc. once every 2 weeks or evolocumab 140 mg sc. once every 2 weeks).

Of these 245 patients, 84 patients received no lipid-lowering pre-treatment, 26 received ezetimibe, 38 received statins, and 97 ezetimibe plus statins. The cholesterol precursor and plant sterols were measured before, and 4-8 weeks after the initiation of alirocumab or evolocumab treatment.

Main results


PCSK9-antibodies strongly reduce non-cholesterol sterols but they do not significantly affect the balance between cholesterol synthesis and absorption, independently of cholesterol-lowering pretreatment. The increase of circulating PCSK9 in response to ezetimibe and statins may partially explain why PCSK9-antibodies are highly effective in reducing LDL-c as an add-on therapy.

The increase in circulating PCSK9 in response to PCSK9 inhibiting treatment was anticipated because the assay used detects PCSK9 bound to evolocumab or alirocumab, and because the main route of PCSK9 clearance, via de LDL-receptor, is blocked by the antibody treatment.


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