Epidemiologic Data Suggest Ceramide Link To CVD Risk

Miriam E. Tucker, for Medscape

April 19, 2022

Researchers published the study covered in this summary on Research Square as a preprint that has not yet been peer reviewed.

Key Takeaways

  • In American Indians (Native Americans) with type 2 diabetes, higher plasma levels of ceramide-16 (ceramide with acylated palmitic acid) associated with a higher rate of cardiovascular disease events, especially CVD events associated with atherosclerosis.

  • The results also suggested other possible associations between plasma levels of sphingolipids and incident CVD events, but the study applied a Bonferroni correction to adjust for multiple comparisons that set a high bar for statistically significant associations with a P value of no greater than 0.0063, based on P less than 0.05/8 for the eight sphingolipid species assessed.

Why This Matters

  • Prior results had independently linked plasma ceramides and sphingomyelins to diabetes risk, glucose levels, insulin levels, and CVD outcomes, but uncertainty remains whether individual sphingolipid species contribute to CVD risk in people with type 2 diabetes.

Study Design

  • The study included people with type 2 diabetes enrolled in two related population-based longitudinal studies that examined CVD incidence and risk factors in several American Indian communities in Arizona, North Dakota, South Dakota, and Oklahoma: the Strong Heart Study and the Strong Heart Family Study.

  • The analysis focused on a prospective cohort of 597 participants in the Strong Heart Family Study with full data available on sphingolipids and CVD events who had 116 incident CVD events over a median 14-year follow-up.

  • The researchers defined CVD events as a first occurrence of myocardial infarction, ischemic stroke, atherosclerotic cardiovascular disease, or heart failure.

  • Analysis of data from the Strong Heart Study used a nested case-control design with 267 participants, including 78 with CVD events during a median 3.8-year follow-up and 189 controls who did not have an incident CVD event.

Key Results

  • In a multivariate model, two investigated sphingolipids significantly associated with greater risk for incident atherosclerotic CVD (ASCVD) events: ceramide (Cer)-16 (hazard ratio [HR], 2.01; P = .0006) and Cer-20 (HR, 1.70; P = .00004).

  • After adjustment for other sphingolipids, neither of these sphingolipids met the Bonferroni threshold for significance. The evidence suggested a possible association between Cer-16 and higher ASCVD risk (HR, 2.26; P = .0276), but not Cer-20 (HR, 1.42; P = .2180).

  • The data showed no significant association between the investigated sphingolipids and incident heart failure.

  • In a meta-analysis of the two cohorts, which collectively included 194 people with incident CVD events, each doubling of plasma Cer-16 significantly associated with a 54% increased rate of composite CVD events.

  • Higher plasma levels of sphingomyelin species with a very-long-chain saturated fatty acid associated with decreased CVD risk but none met the prespecified threshold for statistical significance.


  • The analysis used a composite CVD measure because limited numbers of individual outcomes didn't allow for separate analyses for each type of outcome.

  • The analysis did not match cases and controls in the Strong Heart Study by study site, which may have introduced unmeasured confounding from differences in diet and lifestyle.


  • The study received no commercial funding.

  • None of the authors had disclosures.  

This is a summary of a preprint research study , "Circulating Ceramides and Sphingomyelins and the Risk of Incident Cardiovascular Disease Among People with Diabetes: The Strong Heart Study," written by researchers primarily based at the University of Washington in Seattle on Research Square, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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