The TyG index and cardiovascular mortality in type 2 diabetes: a mediation analysis of renal function in two prospective cohorts

Abstract

The triglyceride-glucose index (TyG), a marker of insulin resistance, has been established as a predictor of cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms linking TyG to cardiovascular disease remain unclear, leaving intervention targets ambiguous. Given the well-established link between insulin resistance and renal dysfunction, we aimed to quantify the mediating role of renal function (eGFR) in the TyG-cardiovascular mortality association, thereby identifying potentially actionable pathways. This study aimed to characterize the complex relationships of renal function and triglyceride-glucose index (TyG) with 5-year cardiovascular mortality in T2DM patients. We analyzed two prospective cohorts of confirmed type 2 diabetes patients from NHANES (2002–2018, n=8842) and Kailuan (2005–2015, n=10,541). TyG was calculated as the logarithmic product of the fasting triglyceride and glucose concentrations. Renal function was defined by the estimated glomerular filtration rate (eGFR). Primary outcome was 5-year cardiovascular mortality. Multivariate Cox regression and causal mediation analysis (using the bootstrap method with 1,000 replications) were conducted to quantify the proportion of the TyG–cardiovascular mortality association mediated by eGFR, adjusting for age, sex, BMI, smoking status, antihypertensive medications, and diabetes duration. The cumulative incidence of 5-year cardiovascular mortality was 5.6% in the NHANES population and 6.1% in the Kailuan cohort. Both higher TyG and lower eGFR were significantly associated with 5-year cardiovascular mortality. Mediation analysis revealed that eGFR mediated 36.3% (NHANES) and 40.2% (Kailuan) of the total effect of TyG on cardiovascular mortality. Furthermore, patients with concurrently elevated TyG index (above cohort-specific median) and eGFR <60 mL/min/1.73 m² had the highest risk of cardiovascular mortality compared to the reference group (TyG ≤ median and eGFR ≥60). This association was consistently observed across both cohorts, with adjusted hazard ratios (HR) of 3.02 (95% CI, 2.54–3.79) in the NHANES cohort and 3.69 (95% CI, 2.95–4.67) in the Kailuan cohort. In T2DM patients, eGFR mediated a substantial proportion of the association between the triglyceride-glucose (TyG) index and cardiovascular mortality. The concomitant presence of an elevated TyG index and reduced eGFR was associated with the greatest risk of cardiovascular mortality. These findings suggest that preserving renal function may attenuate TyG-related cardiovascular risk, underscoring the need for integrated cardiorenal metabolic management in high-risk T2DM patients.