Triglyceride-glucose index in predicting gastric cancer prognosis: A need for caution

Abstract

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Accurate prognostic assessment, which is essential for enhancing overall survival (OS), currently depends on pathologic and clinical staging. This underscores the urgent need for reliable and real-time prognostic biomarkers. The triglyceride-glucose (TyG) index, a readily available marker of insulin resistance, has recently emerged as a potential prognostic tool in GC. Numerous studies have consistently shown a significant association between elevated TyG levels and inferior OS as well as progression-free survival. Despite these promising findings, several challenges must be addressed before the TyG index can be widely adopted in clinical practice. Firstly, the TyG index lacks cancer-specificity, reflecting broader metabolic disturbances commonly observed in conditions such as obesity, diabetes, and cardiovascular disease. This lack of specificity complicates its interpretation in oncological settings. Additionally, the cutoff values for TyG index vary across studies, hindering the establishment of a standardized threshold for clinical application. While the TyG index provides valuable insights into a patient's metabolic health, its limited cancer specificity necessitates cautious use when evaluating the prognosis of GC treatment.

Key Words: Triglyceride-glucose index; Gastric cancer; Prognostic biomarker; Glycolipid metabolism; Overall survival; Progression-free survival

Core Tip: The triglyceride-glucose index, a straightforward marker of insulin resistance, demonstrates potential as a prognostic tool for gastric cancer, correlating with diminished overall survival and progression-free survival. However, its limited cancer specificity, inconsistent cutoff values, and ambiguous mechanistic role in tumor progression necessitate cautious interpretation. Future research should aim to integrate the triglyceride-glucose index with other cancer-specific biomarkers to enhance prognosis prediction and tailor treatment strategies. Prospective, multicenter studies are crucial for validating its clinical utility.

TO THE EDITOR

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with approximately one million new cases diagnosed annually and a notably high mortality rate in East Asia[1-3]. Despite significant advancements in diagnostic techniques and therapeutic strategies, including chemotherapy, targeted therapy, and immunotherapy, the prognosis for patients with advanced GC remains poor. The 5-year survival rate for advanced GC patients is typically less than 30%, underscoring the substantial challenges in managing this disease[4,5]. This unfavorable prognosis is partly attributed to the absence of effective real-time biomarkers for predicting GC prognosis, highlighting the urgent need for reliable biomarkers to facilitate early detection, prognosis prediction, and monitoring treatment response. Recent research conducted by Yao et al[6] has shown improved outcomes in advanced GC patients with a high triglyceride-glucose (TyG) index when treated with combined immunotherapy and chemotherapy. These findings suggest that the TyG index may serve as a valuable prognostic indicator for advanced GC patients.

In recent years, the TyG index, a simple and cost-effective marker of insulin resistance (IR), has attracted growing attention as a potential prognostic indicator in GC. The TyG index is calculated by taking the natural logarithm of the product of fasting triglyceride and glucose levels. Extensive research has demonstrated that elevated TyG index values are associated with poorer overall survival (OS) and progression-free survival in GC patients[7-9]. Given its accessibility and cost-effectiveness, the TyG index shows promise for predicting GC prognosis, particularly in resource-limited settings. However, several significant challenges must be addressed before it can be universally integrated into clinical practice. These challenges encompass its lack of cancer specificity, variability in cutoff values, and the necessity for a more comprehensive understanding of the mechanisms by which IR contributes to cancer progression (Figure 1). This editorial critically evaluates the potential of the TyG index in predicting GC prognosis, delineates its limitations, and underscores the need for further research to establish its clinical utility.

Figure 1 The triglyceride-glucose index, derived from fasting glucose and triglyceride levels, has emerged as a promising prognostic indicator for gastric cancer. Insulin resistance (IR) characterized by chronic hyperglycemia and hyperinsulinemia, modulates key signaling pathways including PI3K/Akt, NF-κB, and AMPK. The triglyceride-glucose (TyG) index may serve as an indirect marker of IR through these pathways, thereby playing a crucial role in various gastric cancer (GC) cell processes including proliferation, apoptosis, invasion, and metastasis. Elevated TyG levels have been correlated with improved overall survival and progression-free survival in GC patients. However, several limitations restrict its broader application, including its lack of cancer specificity, inconsistent cutoff values across studies, and the poorly understood mechanisms by which IR influences cancer progression. This article highlights the necessity of a multifactorial approach to enhance prognostic accuracy and guide personalized treatment strategies. Future research is imperative to validate the clinical utility of the TyG index and investigate its integration with other biomarkers to optimize patient outcomes in GC. TyG: Triglyceride-glucose; OS: Overall survival; PFS: Progression-free survival.

ROLE OF TYG INDEX IN PREDICTING CANCER PROGNOSIS

The TyG index, calculated from fasting triglycerides and fasting glucose levels, serves as a marker of IR. This index reflects disturbances in both glucose and lipid metabolism, which are critical factors in cancer progression[10,11]. IR, characterized by a diminished capacity of insulin to facilitate glucose uptake and utilization in tissues, has been implicated in multiple aspects of tumor biology, including tumor growth, angiogenesis, metastasis, and immune evasion[12-14]. In GC, IR is thought to enhance tumor aggressiveness and contribute to suboptimal treatment outcomes by fostering a metabolic environment that supports tumor progression[7,13,15].

The TyG index, a biomarker of IR, plays a crucial role in GC cell processes such as proliferation, apoptosis, invasion, and metastasis. IR contributes to chronic hyperglycemia and hyperinsulinemia, which modulate key signaling pathways including PI3K/Akt, NF-κB, and AMPK[16,17]. These pathways promote cancer cell survival and growth by regulating genes involved in the cell cycle, driving tumor progression. Furthermore, elevated glucose and triglyceride levels, characteristic of IR, induce the release of inflammatory cytokines that facilitate tumor migration. Activation of AMPK helps mitigate IR by inhibiting NF-κB-driven inflammation and enhancing PI3K/Akt signaling, thus improving insulin sensitivity. Additionally, AMPK influences the PI3K/Akt axis to regulate apoptosis and inflammatory responses. The metabolic alterations associated with IR also contribute to epithelial-to-mesenchymal transition, a critical step in cancer cell invasion and metastasis[18,19]. Studies indicate that a higher TyG index is correlated with increased visceral obesity in GC patients, suggesting its potential role in disease prognosis through metabolic pathways[20]. These findings highlight the significant relationship between the TyG index, IR, and cancer progression.

The association between IR and adverse prognosis in cancer has been extensively documented across various malignancies. For instance, in colorectal cancer, hyperinsulinemia, a hallmark of IR, has been correlated with poorer survival outcomes[21]. Similarly, in breast cancer, IR is associated with enhanced metastasis and chemotherapy resistance[22]. In GC, studies have demonstrated that IR significantly contributes to tumor metastasis and immune suppression[15,23]. Consequently, the TyG index, as an indirect marker of IR, may serve as a valuable tool for predicting GC prognosis by reflecting the metabolic conditions that drive cancer progression.

Several studies have underscored the prognostic significance of the TyG index across various cancer types or post-surgery settings[8,24,25]. In a study by Cai et al[8], even after adjusting for tumor tumor-node-metastasis stage, patients with lower TyG levels exhibited significantly shorter OS compared to those with higher TyG levels. These findings are consistent with the research conducted by Yao et al[6], which established a correlation between higher TyG levels and improved survival outcomes. Conversely, Qin et al[25] and Song et al[24] reported that higher TyG levels were associated with poorer disease control in patients who underwent nephrectomy for renal cell carcinoma and those with pancreatic ductal adenocarcinoma. This evidence underscores a context-dependent relationship between the TyG index and prognosis, potentially aiding in the identification of high-risk patients who may benefit from more aggressive treatments or closer monitoring.

Further supporting the prognostic value of the TyG index, a study by Li et al[26] demonstrated that hyperglycemia can impair the efficacy of chemotherapeutic drugs through altered drug metabolism and an enhanced anti-apoptotic response in tumor cells. Additionally, hyperglycemia has also been shown to be associated with cellular IR[27]. These findings collectively indicate a potential mechanistic link between hyperglycemia, IR, and tumor cell apoptosis, highlighting the potential of the TyG index in predicting chemoresistance in GC. Given the limited treatment options for advanced GC, integrating this insight into clinical decision-making is crucial.

In addition to its prognostic potential, the TyG index may also provide valuable insights into patients’ metabolic health. IR, which is associated with obesity and type 2 diabetes - both significant risk factors for GC, can further elevate GC risk through shared risk factors[28]. Consequently, the TyG index could serve as an effective tool for early identification of these disease-related risk factors. A recently published study on the association between the TyG index and the prevalence of contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI) supports this perspective[29]. In PCI patients, a high TyG index is correlated with a greater likelihood of post-procedural kidney function decline. This phenomenon may be attributed to IR, often accompanying a high TyG index, which can exacerbate inflammation and oxidative stress, thereby increasing the risk of cardiovascular events and diabetes, ultimately affecting long-term patient prognosis. Integrating the TyG index into routine clinical assessments may facilitate the early detection and management of metabolic abnormalities, thereby improving patients' long-term outcomes.

CHALLENGES IN USING TYG INDEX AS A PROGNOSTIC MARKER

Although the TyG index holds considerable potential, several challenges need to be addressed before it can be routinely employed as a reliable prognostic marker for GC. These challenges include its limited specificity to cancer, variability in cutoff values across studies, and uncertainty regarding the role of IR in GC progression[30].

Lack of cancer specificity

The most significant limitation of the TyG index is its lack of cancer specificity. Elevated TyG levels, which indicate IR, are frequently associated with obesity, type 2 diabetes, and cardiovascular disease[31] - conditions that are commonly comorbid in cancer patients[32-34]. Consequently, elevated TyG levels may reflect generalized metabolic dysfunction rather than cancer-specific alterations, thereby limiting its utility as a cancer-specific prognostic marker.

For instance, both obesity and diabetes are established risk factors for adverse outcomes in GC, conditions closely linked to IR[35]. Metabolic syndrome, characterized by abdominal obesity, IR, and dyslipidemia, has been correlated with poorer survival outcomes in GC patients[36]. Therefore, the elevated TyG levels observed in certain GC patients may serve as an indicator of these comorbidities rather than directly reflecting tumor behavior.

To mitigate this limitation, the TyG index should be utilized in conjunction with other cancer-specific biomarkers, such as programmed death ligand 1 (PD-L1) expression, tumor mutational burden, and immune cell infiltration, to enhance its prognostic accuracy. Integrating the TyG index with these biomarkers could offer a more comprehensive evaluation of tumor characteristics and metabolic status, thereby refining treatment strategies and improving patient outcomes.

Variability in cutoff values

Another significant challenge is the variability in cutoff values used to define "high" or "low" TyG levels, with thresholds ranging from 1.4 to 1.75 or higher across studies. This inconsistency hampers the establishment of standardized clinical thresholds[6,8]. The discrepancies in cutoff values may be attributable to variations in study populations or diagnostic methodologies, which are understandable but nonetheless pose challenges for standardization. However, it must be acknowledged that this inconsistency does indeed hinder the establishment of standardized thresholds for clinical application. To address this issue, meta-analyses and multicenter trials should be conducted to harmonize TyG index cutoff values across diverse populations and treatment regimens. Such efforts would facilitate the establishment of an optimal threshold that accurately predicts survival outcomes in GC patients, thereby enhancing clinical decision-making.

Mechanistic uncertainty

Although the TyG index has been associated with an unfavorable prognosis in GC, the precise mechanisms by which IR influences cancer progression remain to be fully elucidated. IR promotes inflammation, oxidative stress, and angiogenesis, all of which can facilitate tumor growth and metastasis[37,38]. However, the exact impact of these metabolic changes on the tumor microenvironment and treatment efficacy remains unclear.

Several studies have indicated that IR may compromise immune cell function, thereby rendering tumors more resistant to immune checkpoint inhibitors[39,40]. This suggests that the TyG index, which indirectly reflects IR, could potentially serve as a predictive marker for immune resistance in GC. Nevertheless, additional research is required to determine whether the TyG index is merely an indicator of metabolic dysfunction or if it actively contributes to tumor progression and treatment resistance in GC.

Retrospective nature of existing studies

The majority of studies investigating the TyG index in GC are retrospective in nature, which introduces potential biases such as selection bias and confounding factors[7,8]. For example, patients with diabetes or obesity may exhibit elevated TyG levels, and these conditions can independently affect survival outcomes. Moreover, retrospective studies lack rigorous control over potential confounding factors, such as chemotherapy type, diagnosis stage, and comorbidities, all of which can influence treatment outcomes.

To address this limitation, it is imperative to conduct prospective, multicenter studies. Such studies would provide a more robust and generalizable comprehension of the TyG index’s role in predicting treatment response and survival outcomes in GC patients. These studies should strive to control for confounding variables and evaluate the synergistic effects of integrating the TyG index with other biomarkers, thereby enhancing its prognostic accuracy.

NEED FOR A MULTIFACTORIAL APPROACH

To address the limitations of the TyG index, researchers are exploring its integration with other biomarkers[30]. For instance, combining the TyG index with inflammation markers (e.g., C-reactive protein) or angiogenesis markers (e.g., vascular endothelial growth factor) within the tumor microenvironment may facilitate a more comprehensive understanding of tumor biology[41]. Additionally, integrating the TyG index with circulating tumor DNA levels or the detection of specific gene mutations (e.g., human epidermal growth factor receptor 2 amplification) could enhance the prediction of therapeutic response and prognosis[42,43]. Furthermore, the combination of the TyG index with PD-L1 expression levels may elucidate mechanisms underlying resistance to cancer immunotherapy[44]. The integration of the TyG index with other biomarkers not only improves prognostic assessment but also guides the development of personalized therapeutic strategies[45]. For instance, patients with a high TyG index may require more stringent metabolic control measures, such as dietary modifications and pharmacological interventions, to improve overall metabolic health.

FUTURE DIRECTIONS

Moving forward, well-designed prospective multicenter studies are essential to validate the TyG index as a reliable prognostic marker in GC[46]. These studies should not only validate its predictive value but also explore its utility in monitoring treatment response, particularly in patients undergoing immunotherapy. Longitudinal studies that track changes in TyG levels over time and correlate these changes with treatment outcomes could provide valuable insights into the interplay among IR, metabolic dysfunction, tumor biology, and immune function[47]. Additional experimental approaches should aim to elucidate the cellular mechanisms through which the TyG influences tumor progression, including its effects on critical signaling pathways such as PI3K/Akt and MAPK, as well as its role in immune evasion. Furthermore, researchers should explore the mechanisms by which TyG interacts with the tumor microenvironment and influences chemotherapy resistance.

Current research has several limitations, including the retrospective nature of many studies, which can introduce bias. Confounding factors such as comorbidities, variations in treatment protocols, and patient demographics need to be carefully considered as they can impact study outcomes. Future research should address these issues to enhance the validity and applicability of the findings. Meta-analyses should standardize TyG index cutoff values and validate its clinical utility across diverse patient populations. This will ensure the TyG index's applicability in various clinical contexts and strengthen evidence for its role in GC prognosis. Additionally, prospective studies should minimize confounding variables through statistical adjustments or selecting homogeneous patient cohorts, thereby improving result accuracy and the TyG index's clinical utility in GC prognosis. Translational challenges involve the progression from biomarker discovery to clinical application. Integrating the TyG index into clinical practice requires addressing issues related to standardization of cutoff values, patient diversity, and logistical barriers in routine clinical settings. Ultimately, combining the TyG index with other biomarkers such as immune markers and circulating tumor DNA could enhance its clinical utility. However, the logistical and technical challenges associated with real-world implementation must be meticulously considered.

CONCLUSION

The TyG index represents a promising and cost-effective tool for evaluating metabolic health and predicting prognosis in GC. However, its application should be approached with caution due to its lack of cancer specificity, variability in cutoff values, and unclear underlying mechanisms. Clinicians can integrate the TyG index into clinical practice by combining it with other cancer-specific biomarkers, such as PD-L1 expression or tumor mutational burden, thereby providing a more comprehensive assessment of prognosis and guiding personalized treatment strategies. Additionally, the TyG index can be utilized as an integral component of routine metabolic screening, especially in resource-limited settings, to facilitate early identification of metabolic abnormalities. Continuous monitoring of TyG levels throughout the course of treatment can assist in the early detection of chemoresistance and inform necessary therapeutic or lifestyle modifications. For patients with elevated TyG levels, metabolic interventions such as dietary modifications or pharmacological treatments (e.g., metformin) should be considered to improve both cancer prognosis and treatment efficacy. Keeping abreast of ongoing research on the TyG index and participating in relevant studies will further refine its role in personalized treatment strategies. Ultimately, as prospective studies continue to validate its utility, the TyG index should be integrated into clinical practice with careful consideration of its potential benefits and limitations.