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

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.