Abstract 12460: The Effect of Alirocumab on the Plasma Metabolome and Lipidome in End-Stage-Renal Disease

Abstract

Introduction: Atherosclerotic disease is the major cause of morbidity and mortality among patients maintained on dialysis for end-stage renal disease (ESRD). Cardiovascular disease specifically accounts for almost 50% of deaths of these patients. In a pilot study to determine the safety of Alirocumab we investigated the plasma metabolome and lipidome in patients on dialysis and after treatment with a PCSK9 inhibitor. Methods: We recruited 14 subjects (10 male/4 female) from outpatient nephrology practices on hemodialysis (n=12) or peritoneal dialysis (n=2) for 3 months without complications. Subjects received Alirocumab (150 mg, i.m.) every 2 weeks. Blood was drawn from 13 subjects at baseline and after 12 weeks (6 injections) at completion of the trial. In addition, blood was drawn from 21 healthy controls. Plasma obtained was stored at -80 o C for biomarker analysis. Targeted metabolomic analysis allowed quantitative detection of 542 metabolites including 480 lipid species in 13 lipid classes. This analysis was performed by liquid chromatography mass spectrometry using the Quant 500 metabolomic kit. Results: Metabolomic analysis identified 152 metabolites significantly different (FDR p&lt0.05) between control and ESRD subjects. Notably, various elevated metabolites as well as lower triglyceride and phosphatidylcholine lipid species. Twenty-three metabolites were significantly decreased after Alirocumab treatment (FDR paired t-test, p&lt0.05), all of which were lipid species from the following classes: cholesterol esters, ceramides, hexosylceramides and sphingomyelins (Figure 1). Conclusions: Subjects with ESRD have dysregulation of lipid metabolism that may contribute to atherosclerosis. The effect of Alirocumab on plasma ceramides and sphingomyelins is of particular interest since increased levels in these lipid species have been shown to be associated with vascular disease and increased mortality.