ANGPTL8, an important regulator of glucose and lipid metabolism, is associated with diabetes, but the role of ANGPTL8 in the outcomes of novel subgroups of diabetes remains unclear. To assess the circulating ANGPTL8 levels in novel subgroups of diabetes and their association with health outcomes, we performed a data-driven cluster analysis (k-means) of patients with newly diagnosed diabetes (741 patients enrolled from 2011 through 2016) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: a longitudinal (REACTION) study. The primary outcomes were mortality from all causes and cardiovascular diseases (CVD), and the secondary outcome was any cardiovascular event. Comparisons among groups were performed using the Kruskal-Wallis test, and the correlations between variables were assessed using the Pearson correlation test. Logistic regression was used to detect associations between the risk of outcomes and the ANGPTL8 levels. We identified four replicable clusters of patients with diabetes that exhibited significantly different patient characteristics and risks of all-cause mortality. The serum ANGPTL8 levels in the cluster of mild age-related diabetes (MARD), severe insulin-resistant diabetes (SIRD), and severe insulin-deficient diabetes (SIDD) were significantly higher than those in the mild obesity-related diabetes (MOD) cluster (685.01 +/- 24.50 vs. 533.5 +/- 18.39, p < 0.001; 649.69 +/- 55.83 vs. 533.5 +/- 18.39, = 0.040; 643.29 +/- 30.89 vs. 533.5 +/- 18.39, p = 0.001). High circulating ANGPTL8 levels were more highly associated with a greater hazard of all-cause mortality (quartile 4 vs 1: risk ratio [RR] 3.23, 95% CI 1.13-9.22; per unit increase in the Z score: RR 1.53, 95% CI 1.17-2.01) than low circulating ANGPTL8 levels. In conclusion, this 5-year follow-up REACTION study revealed that the circulating ANGPTL8 levels show differences among novel subgroups of adult patients with diabetes and are associated with all-cause mortality in the subsequent 5 years.