Background:
Ceramides are novel lipid biomarkers that robustly predict cardiovascular (CV) disease and major adverse CV events. Given that ceramide levels predict onset of type 2 diabetes and contribute to cardiac complications in diabetics, we evaluated the predictive value of plasma ceramides for CV mortality in subjects with type 2 diabetes and coronary artery disease (CAD).

Methods:
We performed a retrospective analysis of 2583 subjects (924 subjects with Type 2 diabetes, 1659 non-diabetic subjects) included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study with angiographically diagnosed CAD. Plasma ceramide profiles were measured using ESI-MS/MS at study inclusion. Univariate and multivariate Cox proportional hazard models were used to assess the association with CV mortality.

Results:
After a median follow-up of 7.7 years, CV mortality was increased in diabetic versus non-diabetic subjects (31.8% versus 15.9%, p<0.05). Using the Cox proportional hazard model adjusted for age, body mass index, lipid lowering therapy, hypertension, dyslipidemia, plasma levels of unsaturated but not saturated ceramides were independently associated with increased CV mortality in non-diabetic subjects (HR 1.48; 95%CI 1.12 – 1.95; p=0.006). This association was even stronger in diabetic individuals (HR 1.61; 95%CI 1.26 – 1.95; p-value <0.001). In addition, diabetic subjects with ceramide levels in the highest quartile showed the strongest association with CV mortality compared to other quartiles (HR 1.46; 95%CI 1.16-1.85; p=0.001).

Conclusions:
Plasma levels of unsaturated ceramides are independently associated with CV mortality in subjects with CAD with a stronger association in individuals with type 2 diabetes, suggesting unsaturated ceramides as a valuable lipid biomarker for individual prediction of CV mortality in subjects with high CV risk.