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Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects

ABSTRACT: Abstract: BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 monoclonal antibody inhibitors (PCSK9mAb) not only reduce low density lipoprotein cholesterol (LDL-C) but can also modulate inflammation. OBJECTIVES: This trial was designed to define the impact of evolocumab on circulating immune cell properties in high-risk ASCVD subjects. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level of >70 mg/dL on maximum tolerated statin therapy to receive either subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were the change in lipoproteins, blood viscosity, and circulating immune cell transcriptional response at 2 weeks and 12 weeks with evolocumab compared with matching placebo. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects (4 evolocumab, 2 placebo) did not receive study medication consistently after the 2-week visit due to suspension of research activities during the COVID-19 pandemic. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p<0.0001) and -52.8% (p<0.0001) at 2 and 12 weeks respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells (PBMC) with and without TLR4 stimulation (“Stress” transcriptomics). There were no group differences in transcriptional profiles in unstimulated PBMC; however, “stress” transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS: This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of “stress” profiling of circulating immune cells that more clearly define immune contributions to ASCVD. (Funded by Amgen Inc.; ClinicalTrials.gov number, NCT03829046).

ORGANISM(S): Homo sapiens

PROVIDER: GSE254732 | GEO | 2025/01/11

REPOSITORIES: GEO

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Project description:Background: We tested the hypothesis that short-term supplementation with a physiological dose of folate can alter global gene expression in the colon of subjects with colorectal adenoma using a randomised double blind placebo controlled trial design. Materials and Methods: Fourteen subjects with histologically confirmed colorectal adenoma, randomised to receive folic acid (400M-BM-5g/d, n=6) or placebo (n=8) for 10 weeks, had blood samples and colonic tissue biopsies collected before and after the intervention. Blood samples were used to determine serum and red cell folate, plasma homocysteine, and genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase (MS A2756G). RNA extracted from normal-appearing colonic tissue samples was used to determine global gene expression in the colon using AffymetrixM-oM-^CM-^R Microarray GeneChips. Microarray results were confirmed by quantitative real time RT-PCR. Two methods were used to analyse the microarray data: (1) differences between pre- and post-intervention gene expression values in the folic acid and placebo groups separately using paired-sample t tests; (2) differences between the folic acid and placebo groups in the ratio of post-intervention to pre-intervention gene expression values using independent sample t-tests. Results: (1) Following intervention, sixty seven genes were up-regulated and 13 genes were down-regulated in the folic acid group, while 21 genes were up-regulated and none were down-regulated in the placebo group (P<0.05, adjusted for multiple testing). (2) Thirty six genes were up-regulated and 18 genes were down-regulated in the folic acid group when compared with placebo, but none of these were statistically significant after adjustment for multiple testing. These genes are involved in multiple pathways, including cell cycle, signal transduction, cell differentiation, transport, cell division, cell motility, protein transport and immune response. There were no genes involved in 1-carbon metabolism that were altered in expression, although several genes involved in neoplasia were up-regulated. Conclusions: These results indicate that while folic acid can modify gene expression, it is difficult to separate its effects from the natural variability in gene expression in the colon. Fourteen patients with colorectal adenoma were treated with either folate supplementation (6 subjects) or a placebo (8 subjects) for 10 weeks in a randomised double-blind trial. Colonic biopsies of normal tissue were taken before and after the intervention, and analysed for gene expression.

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Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects

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