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

Lutjohann, Dieter; Stellaard, Frans; Boeluekbasi, Bediha; Kerksiek, Anja; Parhofer, Klaus G. und Laufs, Ulrich (2021): Anti-PCSK 9 antibodies increase the ratios of the brain-specific oxysterol 24S-hydroxycholesterol to cholesterol and to 27-hydroxycholesterol in the serum. In: British Journal of Clinical Pharmacology, Bd. 87, Nr. 11: S. 4252-4261

Abstract

Aims 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. Methods 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. Results 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 mu g 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). Conclusion 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0306-5251
• Sprache: Englisch