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

Aim: The 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.

Methods: Analyses 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.

Results: Lipidomics 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.

Conclusion: Fenofibrate 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.