Abstract 12468: One-Year Effects of Randomized High-Intensity Statin versus Placebo on the Bioactive Lipidome: Findings From the JUPITER Trial

Abstract

Introduction: Statin effects extend LDL-C reduction, with the potential to modulate the metabolism of bioactive lipids (BALs), crucial metabolites for biological signaling and inflammation. Hypothesis: Statin allocated participants will have a different BAL profile with cardioprotective properties compared to placebo. Aim: To investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (NCT00239681), a randomized double-blinded primary prevention trial involving individuals with LDL-C <130 mg/dL and high-sensitivity C-reactive protein ≥ 2 mg/L. Methods: Using a non-targeted mass spectrometry approach, over 15500 lipid features were assayed from baseline (BL) and 1-year (Y1) plasma samples from non-CVD cases from 2 nested JUPITER sub-studies: JUPITER discovery (N=589) and JUPITER validation (N=409). The effect of rosuvastatin 20mg vs . placebo on BALs was examined by fitting a linear regression with delta values (ΔBAL=BAL Y1 -BAL BL ) that adjusted for age (years) and baseline BAL level. Significant associations in discovery were carried over for validation. Multiple comparisons were adjusted using a two-stage overall False Discovery Rate (FDR) <.05. Results: We identified 569 associations significantly validated (overall FDR<.05), including 27 BALs with putative annotation. Statins increased levels of 302 BALs, such as specialized pro-resolving mediators (SPMs) and eicosanoids with anti-inflammatory activity in the vasculature (e.g. 5,6-diHETE), arterial vasodilation properties (hepoxilins), and a precursor of leukotrienes (5-HpETE). Among 267 BALs lowered by statins, there were arachidonic acid and inflammation-related lipid mediators (10 HDoHE, 5-HEPE, 11-HETE, 9-HODE, 11d-TXB2) (Fig1 A and B). Conclusions: Statins had pleiotropic effects on BAL metabolites, predominantly increasing anti-inflammatory and pro-resolution BALs and decreasing BALs with pro-inflammatory properties.