Abstract
BACKGROUND: ANGPTL8 (angiopoietin-like protein 8) regulates lipid metabolism, but its role in atherosclerosis among patients with type 2 diabetes, particularly through lipid-independent mechanisms, remains unclear. METHODS: This matched case-control study included 202 patients with type 2 diabetes (101 with atherosclerosis, and 101 without) matched for age, body mass index, and sex. Atherosclerosis was assessed via carotid intima-media thickness and plaque scores. Circulating ANGPTL8 levels were measured by ELISA. Associations were evaluated using multivariate logistic regression, restricted cubic splines, and mediation analyses. RESULTS: Patients with atherosclerosis had significantly higher circulating ANGPTL8 levels (529.96 [350.58-816.78] versus 470.62 [265.54-717.47] pg/mL; P=0.027). After adjusting for confounders, the highest ANGPTL8 quartile showed 3.71-fold increased atherosclerosis risk (95% CI, 1.52-9.06; P=0.004) versus the lowest quartile. Each SD increase in ANGPTL8 was associated with 56% higher risk (odds ratio, 1.56 [95% CI, 1.18-2.05]). A significant linear dose-response relationship was observed (P=0.036). Adding ANGPTL8 to traditional risk factors significantly improved discrimination (area under the curve, 0.62 [95% CI, 0.54-0.70]) and reclassification (net reclassification improvement, 0.40 [95% CI, 0.13-0.66]; P<0.001) for atherosclerosis prediction. Mediation analysis revealed that cystatin C partially mediated (8.22%) the effect of ANGPTL8 on atherosclerosis, whereas triglycerides showed negligible mediation. CONCLUSIONS: Elevated ANGPTL8 levels are independently associated with increased atherosclerosis risk in patients with type 2 diabetes. This relationship is partially mediated through cystatin C but not lipid parameters. ANGPTL8 significantly improves cardiovascular risk prediction beyond traditional risk factors, suggesting its potential as a novel biomarker for cardiovascular risk stratification and a therapeutic target addressing residual cardiovascular risk through lipid-independent inflammatory pathways in type 2 diabetes.