Association Between Circulating ANGPTL8 Levels And Clinical Outcomes

Background:ANGPTL8,an important regulator of lipid metabolism,was proved with additional intracellular and receptor-mediated functions recently.This study aimed to investigate circulating levels of ANGPTL8 and its potential associations with risk of kidney function decline in a cohort study.Methods:We analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort(4C)Study.Kidney function decline defined as estimated glomerular filtration rate(eGFR)less than 60 mL per minute per 1.73 m~2 of body-surface area,a decrease in eGFR of?30%from baseline,chronic kidney disease(CKD)-related hospitalization or death,or end-stage renal disease.Association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models.Results:There were 136(5.9%)cases of incident kidney function decline over a median of3.8 years of follow-up.We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to control subjects(718.42±378.17 vs.522.04±283.07 pg/mL,p<0.001).Compared with the first quartile,multivariable-adjusted hazard ratios(95%confidence intervals[CIs])for kidney function decline was2.56(95%CI,1.39-4.73)for the fourth ANGPTL8 quartile.Furthermore,compared with the first ANGPTL8 quartile,those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD(Relative risk:1.42;95%CI,1.07-1.89).Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline(p for nonlinear trend=0.66,p for linear trend<0.001).Conclusions:Participants with higher circulating ANPTL8 levels had increased risks for kidney function decline.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.We conducted this study 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 China Cardiometabolic Disease and Cancer Cohort(4C)Study,a longitudinal 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(MACE),hospitalization for heart failure(HF),and kidney function decline.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).Multivariable-adjusted binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with greater risk ratios(RRs)of primary outcome(RR in quartile 4 vs.quartile 1,3.54;95% CI 1.32-9.50)but not associated with secondary outcome(RR,Q4 vs.Q1,1.49;95% CI 0.81-2.75)in diabetic patients.In control group,ANGPTL8 levels were not associated with primary(RR,Q4 vs.Q1,1.32;95% CI 0.25-7.06)or secondary outcome(RR,Q4 vs.Q1,1.45;95% CI 0.56-3.71).Further analyses for composite of secondary outcome showed that ANGPTL8 levels were associated with increased risk for kidney function decline(RR in quartile 4 vs.quartile 1,4.75;95% CI 1.30-17.39)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.Background: ANGPTL8,an important regulator of glucose and lipid metabolism,is associated with diabetes,but the role of ANGPTL8 in novel subgroups of diabetes remains unclear.Methods: To assess the circulating ANGPTL8 levels in novel subgroups of diabetes and their association with health outcomes,we performed a data-driven cluster analysis(kmeans)of patients with newly diagnosed type 2 diabetes(741 patients enrolled from 2011 through 2016)from the China Cardiometabolic Disease and Cancer Cohort(4C)study.Comparisons among groups were performed using the Kruskal-Wallis test,and the correlations between variables were assessed using the Spearman correlation test.Binary logistic regression analysis was conducted to calculate risk ratios(RRs)and 95% confidence intervals(CIs)for clinical outcomes in quartiles of ANGPTL8.Results: We identified four replicable clusters of 741 patients with diabetes that exhibited significantly different patient characteristics.The 294(39.7%)patients in the cluster of mild age-related diabetes(MARD)were older than patients in other clusters,but characterized by relatively low body mass index(BMI)and high all-cause mortality.The mild obesity-related diabetes(MOD),including 281(37.9%)patients,was also characterized by early-onset disease,obesity but not by insulin resistance,and showed only modest metabolic derangements.The all-cause and cardiovascular mortality and morbidity of chronic kidney diseases in MOD were lower than other clusters.The severe insulinresistant diabetes(SIRD),including 51(6.9%)patients was characterized by insulin resistance and high BMI.The 115(15.5%)patients in the cluster of severe insulin-deficient diabetes(SIDD)were characterized by low age at onset,relatively low BMI,low insulin secretion and poor metabolic control.The serum ANGPTL8 levels in MARD,SIRD,and SIDD were significantly higher than those in the MOD cluster(685.01 ± 24.50 vs.533.56 ± 18.39 pg/mL,p < 0.001;649.69 ± 55.83 vs.533.5 ± 18.39 pg/mL,p = 0.04;643.29 ± 30.89 vs.533.5 ± 18.39 pg/mL,p = 0.001).After controlling for multiple variables,the ANGPTL8 levels were positively correlated with age(r = 0.18),fasting blood glucose(FPG)(r = 0.08),2 h plasma glucose concentration(2h PG)(r = 0.08),triglycerides(TG)(r = 0.12),aspartate aminotransferase(AST)(r = 0.11)and creatine(r = 0.11),and negatively correlated with estimated glomerular filtration rate(eGFR)(r =-0.13)(all p ? < 0.05)in all patients.Compared with the first quartile,multivariable-adjusted hazard ratios(95% confidence intervals [CIs])for all-cause mortality was 3.23(95% CI,1.13-9.22)for the fourth ANGPTL8 quartile.Conclusion: In conclusion,our study revealed that the circulating ANGPTL8 levels show differences among novel subgroups of adult patients with diabetes and its correlation with age,FPG,TG and creatine may contribute to the differences of characteristics and clinical outcomes in novel subgroups.