BackgroundElevated triglyceride-glucose (TyG) index and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are independently associated with increased risk of major adverse cardio-cerebral events (MACCEs) in diabetic patients with the acute coronary syndrome (ACS), but have not been evaluated jointly. We sought to investigate the independent and joint association of the TyG index and NT-proBNP with MACCEs risk.MethodsData from 5046 patients with diabetes and ACS were recorded in the Cardiovascular Center Beijing Friendship Hospital Database Bank between 2013 and 2021, including measurements of fasting triglycerides, plasma glucose, and NT-proBNP. The TyG index was calculated as Ln (fasting triglycerides [mg/dL] × fasting plasma glucose [mg/dL]/2). Associations of the TyG index and NT-proBNP with MACCEs risk were assessed using flexible parametric survival models.ResultsDuring 13589.9 person-years of follow-up, 985 incident MACCEs of the 5046 patients (65.6 years of age and 62.0% men) were observed. Elevated TyG index (HR: 1.18; 95% CI 1.05‒1.32 per 1 unit increase) and NT-proBNP categories (HR: 1.95; 95% CI: 1.50‒2.54 for > 729 pg/ml compared to < 129 pg/ml) were independently associated with MACCEs risk in the fully adjusted model. According to the joint categories of the TyG index and NT-proBNP, patients with the TyG index > 9.336 and NT-proBNP > 729 pg/ml were at the highest risk of MACCEs (HR: 2.45; 95% CI 1.64‒3.65) than the ones with TyG index < 8.746 and NT-proBNP < 129 pg/ml. The test for interaction was not significant (Pinteraction= 0.49). Incorporating these two biomarkers into the established clinical model, the Global Registry of Acute Coronary Events (GRACE) risk score, resulted in a significant improvement in risk stratification.ConclusionsThe TyG index and NT-proBNP were independently and jointly associated with the risk of MACCEs in patients with diabetes and ACS, suggesting that patients with both markers elevated should be aware of the higher risk in the future.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12933-023-01890-9.