Circulating Ceramides and Sphingomyelins and the Risk of Incident Cardiovascular Disease Among People with Diabetes: The Strong Heart Study

Background: Plasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes. Methods: : This analysis included participants with prevalent diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case-control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 6-7 years prior to sphingolipid measurement in both cohorts. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis. Results: : There were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with increased CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI: 1.05-3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with decreased CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI: 0.26-0.87), although none of the associations met our pre-specified threshold for statistical significance of p=0.006. Conclusions: : While replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only increase diabetes risk, but may also increase CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes.