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

Abstract

Background: ANGPTL8, an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance. However, the role of ANGPTL8 in the outcomes of diabetic patients remains unclear. This study aimed to investigate circulating levels of ANGPTL8 in participants with and without diabetes and its potential associations with clinical 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 were generated on the basis of age, sex and body mass index at baseline. The primary outcome was all-cause mortality. The secondary outcomes were 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 diabetic patients and control subjects. Serum ANGPTL8 levels were elevated in patients with diabetes compared to control subjects (618.82 318.08 vs 581.20 299.54 pg/mL, p =0.03). 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, 3.54; 95% CI 1.32 – 9.50) and renal dysfunction (RR in quartile 4 vs quartile 1, 12.43; 95% CI 1.48 – 104.81) only in diabetic patients. Multivariable-adjusted restricted cubic spline analyses revealed 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 control subjects (p for nonlinear trend =0.26, p for linear trend =0.80). According to ROC curve analysis, the inclusion of ANGPTL8 in QFrailty score significantly improved its predictive performance for mortality in patients with diabetes. Conclusion: Serum ANGPTL8 levels were associated with an increased risk of all-cause mortality and could be used as a potential biomarker for the prediction of death in patients with diabetes.

ANGPTL8 in metabolic homeostasis: more friend than foe?

“…Although current studies suggest that ANGPTL8 may be a harmful molecule; that is, elevated baseline ANGPTL8 levels are associated with a higher risk of retinopathy and all-cause mortality in patients with T2DM [20][21][22]. At the same time, inhibition of ANGPTL8 appears to be beneficial, manifested by a decrease in circulating triglycerides [112].…”

“…The results of clinical prospective study also showed that the baseline ANGPTL8 level was negatively correlated with the risk of metabolic syndrome, even after multivariable adjustment [19]. Paradoxically, the results of another prospective study showed that the baseline ANGPTL8 level was positively correlated with the risk of retinopathy and all-cause mortality in patients with T2DM [20][21][22]. Similarly, a protein truncation variant (PTV) of ANGPTL8 has been shown to reduce the incidence of coronary artery disease (CAD) in a Finnish population [23], while another study has shown a significant reduction in cardiovascular events in CAD patients with high ANGPTL8 levels [24].…”