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

  • Campesterol (r=0.37; P<0.001), sitosterol (r=0.23; P <0.001), and lathosterol (r=0.45; P <0.001) were positively related to total cholesterol.
  • The campesterol- and sitosterol-to-cholesterol ratios were strongly and positively correlated (r=0.80; P <0.001).
  • The campesterol- (r= -0.14; p =0.024) and sitosterol- (r= -0.20; P <0.001) to-cholesterol ratios were inversely related to the lathosterol-to-cholesterol ratio.
  • Circulating PCSK9 increased in parallel with the potency of lipid lowering treatment and was highest in the ezetimibe plus statin group. Total cholesterol, LDL-c, and triglyceride levels were highest in the group without pretreatment and lowest in the ezetimibe plus statin group.
  • Compared with those without pretreatment, the statin group and the ezetimibe plus statin groups had lower lathosterol and lathosterol-to-cholesterol ratios (all P <0.001).
  • In response to treatment with PCSK9-antibodies, circulating PCSK9 strongly increased in all groups, whereas total cholesterol, triglycerides, and LDL-c decreased in all groups.
  • No significant differences were seen among the 4 pretreatment groups in the responses to PCSK9-antibodies of the lathosterol-, campesterol-, and sitosterol-to-cholesterol ratios and the campesterol- and sitosterol-to-lathosterol ratios.


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.


1. Sabatine, M. S., R. P. Giugliano, A. C. Keech, et al; FOURIER Steering Committee and Investigators. 2017. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med.376:1713-1722.

2. Silbernagel, G., G. Fauler, W. Renner, et al. 2009. The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease. J. Lipid Res.50:334-341.

3. Silbernagel, G., G. Fauler, M. M. Hoffmann, et al. 2010. The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality. J. Lipid Res.51:2384-2393.

Find this article online at J Lipid Res

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