Fenofibrate decreases plasma ceramide in type 2 diabetes patients: A novel marker of CVD?

Abstract

AimThe benefit of the lipid-lowering drug fenofibrate on cardiovascular outcomes is controversial. Our aim was to find new circulating markers to identify those patients most likely to benefit from fenofibrate prescription. MethodsAnalyses were conducted of plasma samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and after fenofibrate treatment (200mg/day). Non-targeted and targeted lipid analyses and apolipoprotein measurements were made using mass spectrometry methods. ResultsLipidomics revealed a global decrease in ceramide after fenofibrate treatment confirmed by quantitative analysis (−18.2%, P<0.001). These changes were strongly associated with those found for plasma sphingomyelin (r=0.80, P<0.001) and, to a lesser extent, for sphingosine-1-phosphate (r=0.34, P<0.001). Ceramide levels decreased in 73.5% of patients. In addition to the expected lipid changes (decreases in triglycerides, total cholesterol and LDL cholesterol, and increase in HDL cholesterol), fenofibrate also lowered plasma apoC-II (−11.1%, P<0.01), apoC-III (−24.6%; P<0.001), apoB100 (−27.0%, P<0.01) and sphingomyelinase (−7.6%, P<0.001), and increased plasma apoA-II (22.4%, P<0.001) as well as adiponectin (11.4%, P<0.001). No significant association was found between ceramide decrease and these modulations except for total cholesterol (r=0.20, P=0.047) and HDL protein components. At baseline, only elevated sphingolipid levels were significantly associated with ceramide reduction after fenofibrate treatment. ConclusionFenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients.