Predictive values of ANGPTL8 on risk of all-cause mortality in diabetic patients: from the REACTION Study

Abstract

Background: ANGPTL8, an important regulator of glucose and lipid metabolism, is increased in diabetes and associated with insulin resistance. However, the role of ANGPTL8 in diabetes outcomes remains unclear. The study aimed to investigate circulating levels of ANGPTL8 in participants with and without diabetes and its potential association with death and cardiovascular and renal outcomes in a 5-year cohort study.Methods: Propensity-matched cohorts of subjects with and without diabetes from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A longitudinal (REACTION) study was generated on the basis of age, sex and body mass index at baseline. The primary outcome was death from any cause. The secondary outcome was a composite of new-onset major adverse cardiovascular events, hospitalization for heart failure and renal dysfunction (eGFR < 60/min/1.73 m2).Results: We identified 769 matched pairs of patients from the diabetes group and the control group. Serum ANGPTL8 levels were elevated in patients with diabetes compared to subjects in the control group (618.82 318.08 vs. 581.20 299.54, p = 0.03). Furthermore, increasing quartiles of ANGPTL8 were associated with increased all-cause mortality in both the control and diabetes groups (all p values < 0.05). Binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with greater risk ratios (RRs) of death (RR in quartile 4 vs quartile 1, 3.47; 95% CI 1.30 – 9.29) and renal dysfunction (RR in quartile 4 vs quartile 1, 10.50; 95% CI 1.32 – 83.60) only in diabetic patients. Multivariable-adjusted restricted cubic spline analyses suggested a significant linear relationship between ANGPTL8 and all-cause mortality in diabetic patients (p for nonlinear trend = 0.99, p for linear trend = 0.01) but not in the controls (p for nonlinear trend = 0.26, p for linear trend = 0.80). According to the ROC curves, the QMortality and QFrailty scores, combined with ANGPTL8, showed better performance in predicting death, especially in diabetic patients.Conclusion: Serum ANGPTL8 levels were associated with an increased risk for all-cause mortality and renal dysfunction in subjects with diabetes. Furthermore, ANGPTL8 had good performance in predicting all-cause mortality in diabetic patients, which may contribute to the early detection of individuals with diabetes at high risk.