Anti-PCSK 9 antibodies increase the ratios of the brain-specific oxysterol 24S-hydroxycholesterol to cholesterol and to 27-hydroxycholesterol in the serum.

Abstract

The serum ratios of the brain-specific oxysterol 24S-hydroxycholesterol (24S-OHC) to cholesterol and to 27-OHC reflect brain cholesterol turnover. We studied the effect of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) that enhance low-density lipoprotein receptor activity on serum cholesterol and oxysterol concentrations. Twenty-eight hypercholesterolaemic patients (15 males and 13 females) responding insufficiently to maximally tolerated statin and/or ezetimibe therapy were additionally subcutanously treated biweekly with either the PCSK9ab alirocumab (150 mg, n =13) or evolocumab (140 mg, n =15). Fasting serum cholesterol was measured by gas chromatography and the oxysterols 24S-OHC and 27-OHC using gas chromatography-mass spectrometry before, after 1-month (n =28) and after 3-month (n =13) treatment. As expected, PCSK9ab treatment lowered serum cholesterol and oxysterol levels after 1 month. The serum ratio of 24S-OHC to cholesterol increased after 1 month by 17 ± 28% (mean ± standard deviation; 95% confidence interval [CI]: 5.8 to 28%; P< .01) and 24S-OHC to 27-OHC by 15 ± 39% (95% CI: 0.2 to 30%; P< .01). Within 3 months, 24S-OHC to cholesterol increased by 2.8 μg g-1 mo-1 (95% CI: 2.1 to 3.6; P< .01) and 24S-OHC to 27-OHC by 0.019 mo-1 (95% CI: 0.007 to 0.032; P< .01). The serum ratios of 24S-OHC to cholesterol and to 27-OHC increased after treatment with PCSK9ab. We hypothesize that this is caused by a reduced entrance of 27-OHC into the brain, increased synthesis of brain cholesterol, increased production of 24S-OHC and its secretion across the blood-brain barrier.