To our knowledge, this study represents the first investigation into the relationship between the TyG index and all-cause mortality among sepsis patients. In this study, we found a significant association between an elevated TyG index and increased in-hospital mortality among patients with sepsis. This conclusion aligns with ICU and 28-day mortality in patients with sepsis, which shown a consistent linear relationship. This association remained robust, even after adjusting for multiple clinical and laboratory variables. Our results extended the application of the TyG index to the realm of cardiovascular disorders, indicating its potential value as a decision-making tool for clinicians managing patients with sepsis.

In recent years, TyG index has been proposed as a potential marker for metabolic disorders, atherosclerotic conditions, cardiovascular disease and COVID-19 [24,25,26,27]. Numerous clinical studies have examined the association between an elevated TyG index and higher morbidity and mortality associated with critically ill patients and infectious diseases across various populations. Yang et al. found that the TyG index was an independent risk factor for in-hospital and ICU mortality in patients after cardiac arrest [7]. Lee et al. observed that the TyG index might be helpful in predicting short-term functional outcomes in critically ill stroke patients undergoing reperfusion therapy [28]. Additionally, for individuals with coronary artery disease, the TyG index could contribute to predicting adverse cardiovascular events [29, 30]. For general population, a high TyG index has been found to be associated with an increased incidence of respiratory symptoms, an elevated risk of chronic lung disease, and a reduction in lung function [31]. These studies collectively suggest the potential of the association between TyG index and clinical outcomes in critically ill and infection-related patients. Other studies have reported that for each unit increase in the TyG index, the risk of in-hospital mortality in critically ill patients increases by nearly 30% or more [8, 9]. We observed that for each unit increase in the TyG index, the risk of in-hospital mortality for sepsis patients increased by 44.0%, our study's conclusions align with previous researches, indicating an association between elevated TyG index and increased mortality.

Our results suggest an association between a high TyG index and the severity and outcomes of sepsis. Sepsis can lead to insulin resistance and the disruption of lipid metabolism accompanied by uncontrolled hyperglycemia and glycemic variability during the acute phase of sepsis. The prognosis of sepsis is closely tied to the severity of inflammatory responses, which are significantly correlated with insulin resistance. Our results demonstrate that the TyG index is positively correlated with disease severity scores. The TyG index reflects the severity of disease in patients with sepsis and provides insights that can contribute to the clinical management of sepsis. Clinicians should be aware of patient blood glucose management and monitor changes in insulin resistance indicators.

The exact biological mechanisms underlying the relationship between the TyG index and sepsis prognosis remain unclear. The TyG index is associated with insulin resistance (IR), insulin resistance has been widely demonstrated to be closely related to endothelial dysfunction, oxidative stress, immune dysregulation, coagulation imbalance, and inflammatory response [32,33,34], all of which are also closely associated with the occurrence and progression of sepsis. From the baseline data, we observed significant differences in SOFA scores among patients in different TyG index groups, indicating a close association between the TyG index and disease severity. Changes in insulin resistance during the acute phase of sepsis could reflect the inflammatory state or severity of sepsis. A potential explanation for the role of the TyG index as an indicator of cardiovascular disease could be that the TyG index serves as a reflection of IR in patients. IR, in turn, can contribute to the development of cardiovascular diseases by enhancing vascular stiffness and diminishing the bioavailability of nitric oxide (NO) [35, 36]. An elevated TyG index is associated with cardiovascular diseases, and the presence of cardiovascular diseases in sepsis is a risk factor contributing to adverse patient outcomes. Although cardiovascular diseases were present in the various TyG index level groups in this study, no differences were observed.

In sensitivity analysis, our study found that the linear relationship between the TyG index and in-hospital mortality in sepsis patients remained consistent in the younger age group, female patients, those with lower BMI, non-hypertensive individuals, and those without congestive heart failure. This result might be attributed to the fact that advanced age, male, higher BMI, and hypertension are traditionally recognized as unfavorable risk factors for sepsis prognosis. Furthermore, factors such as Gender, obesity, and cardiovascular disease can contribute to insulin resistance, potentially leading to an underestimation of the association between the TyG index and sepsis outcomes. Meanwhile, in subgroup analyses and regarding the 28-day mortality and ICU mortality, we observed that after stratifying by SOFA score and gender, the results were not statistically significant. After stratified analysis, the sample size decreases, leading to a reduction in effect size, which can be one of the reasons for non-significant results. However, the consistent direction of all results indicates the stability and reliability of the core outcomes. In patients with complete SOFA scores, the relationship between the TyG index group and in-hospital ICU, and 28-day mortality remained stable. In Cox regression analysis, the relationship between 28-day and 90-day mortality rates in the TyG index group was consistent with core results. Furthermore, we performed a feature analysis utilizing SHAP and Brouta plots, and the importance of the TyG index as a feature was evaluated within the outcome prediction model. Consequently, a machine learning prognostic model for sepsis could be established in the future by focusing on the TyG index.

However, it is important to acknowledge the limitations of this study. First, our analysis was retrospective and derived from observational data, precluding the definitive establishment of causality. Nonetheless, we employ a range of rigorous statistical methods to yield robust and credible outcomes. Second, the TyG index was not dynamically monitored, and sepsis itself could influence lipid metabolism and blood glucose fluctuations. The TyG index obtained from the first-time glucose and triglyceride measurements may not comprehensively represent insulin resistance in the body. Third, some confounding factors, including metabolic syndrome parameters, Acute Physiology and Chronic Health Evaluation II (APACHE II), nutritional state parameters, and inflammatory markers, were not thoroughly considered. This may have an impact on the results. Fourth, clinicians were following different guidelines with different definitions of sepsis from 2008 to 2019, which could potentially impact the study results. Fifth, when patients receive enteral or parenteral nutrition, it may impact lipid and glucose levels, potentially leading to an increase in the TyG index. However, with the large sample size included in our study, this effect is likely mitigated. Further research is needed to investigate the key mechanisms of insulin resistance in patients with sepsis.