Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

• Main Authors: Alessandro Di Minno, Roberta Clara Orsini, Mattia Chiesa, Viviana Cavalca, Ilenia Calcaterra, Maria Tripaldella, Andrea Anesi, Susanna Fiorelli, Sonia Eligini, Gualtiero I. Colombo, Elena Tremoli, Benedetta Porro, Matteo Nicola Dario Di Minno
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Biomedicines
• Subjects: PCSK9; untargeted metabolomics; familial hypercholesterolemia
• Online Access: https://www.mdpi.com/2227-9059/9/8/1073

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, <i>p</i> < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (<i>p</i>-value = 0.041), indole (<i>p</i>-value = 0.045), and indoleacrylic acid (<i>p</i>-value= 0.045) concentrations. Conversely, significant decreases in choline (<i>p</i>-value = 0.045) and phosphatidylcholine (<i>p</i>-value < 0.01) together with a reduction in platelet activating factor (<i>p</i>-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.