Plasma Ceramides Predict All-Cause and Cause-Specific Mortality in Individuals With Type 2 Diabetes

Abstract

Abstract Context The Cardiovascular Event Risk Test (CERT1) score derived from plasma ceramides has been applied clinically for cardiovascular risk assessment. Objective To study whether plasma ceramides predict risk of mortality in patients with type 2 diabetes. Methods In a prospective study that included 1903 outpatients with type 2 diabetes in a regional hospital and a primary care facility in Singapore, plasma ceramides (d18:1/16:0, d18:1/18:0, d18:1/24:0, d18:1/24:1) were measured by mass spectrometry and CERT1 score was calculated accordingly. Main outcomes were all-cause and cause-specific mortality. Results During a median of 9.3 years of follow-up, 252 death events were identified. Compared to those with low score (≤ 2), participants with a high CERT1 score (≥ 7) had 1.86-fold (95% CI, 1.30-3.65) increased risk for all-cause death after adjustment for cardiorenal risk factors, including estimated glomerular filtration rate and albuminuria. As continuous variable, 1-unit increment in CERT1 was associated with 8% increased risk for all-cause death (adjusted hazard ratio [HR] 1.08 [1.04-1.13]). Adding CERT1 onto Risk Equations for Complications Of type 2 Diabetes (RECODe) mortality risk engine significantly improved prediction of 10-year risk of all-cause death (area under the curve, 0.810 to 0.823, delta 0.013 [0.005-0.022]). The association between CERT1 and noncardiovascular death remained significant (adjusted HR 2.12 [1.32-3.42]), whereas its association with cardiovascular death became nonsignificant after adjustment for kidney measurements (adjusted HR 1.41 [0.78-2.56]). Conclusion CERT1 score predicts mortality risk independent of clinical cardiorenal risk factors. Further studies are warranted to elucidate the mechanistic linkage between ceramide and mortality, especially noncardiovascular mortality.