Interplay of serum biomarkers bilirubin and γ-glutamyltranspeptidase in predicting cardiovascular complications in type-2 diabetes mellitus

Abstract

This editorial synthesizes insights from a series of studies examining the interplay between metabolic and oxidative stress biomarkers in cardiovascular disease (CVD), focusing particularly on type-2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS). The central piece of this synthesis is a study that investigates the balance between oxidative stress and antioxidant systems in the body through the analysis of serum bilirubin and γ-glutamyltranspeptidase (γ-GGT) levels in T2DM patients with ACS. This study highlights serum bilirubin as a protective antioxidant factor, while elevated γ-GGT levels indicate increased oxidative stress and correlate with major adverse cardiovascular events. Complementary to this, other research contributions reveal γ-GGT’s role as a risk factor in ACS, its association with cardiovascular mortality in broader populations, and its link to metabolic syndrome, further elucidating the metabolic dysregulation in CVDs. The collective findings from these studies underscore the critical roles of γ-GGT and serum bilirubin in cardiovascular health, especially in the context of T2DM and ACS. By providing a balanced view of the body’s oxidative and antioxidative mechanisms, these insights suggest potential pathways for targeted interventions and improved prognostic assessments in patients with T2DM and ACS. This synthesis not only corroborates the pivotal role of γ-GGT in cardiovascular pathology but also introduces the protective potential of antioxidants like bilirubin, illuminating the complex interplay between T2DM and heart disease. These studies collectively underscore the critical roles of serum bilirubin and γ-GGT as biomarkers in cardiovascular health, particularly in T2DM and ACS contexts, offering insights into the body’s oxidative and antioxidative mechanisms. This synthesis of research supports the potential of these biomarkers in guiding therapeutic strategies and improving prognostic assessments for patients with T2DM and some CVD.

Key Words: Type-2 diabetes mellitus; Acute coronary syndrome; Serum biomarkers; γ-glutamyltranspeptidase; Bilirubin; Cardiovascular disease

Core Tip: This editorial delves into the predictive value of serum biomarkers such as bilirubin and γ-glutamyltranspeptidase in the context of type-2 diabetes mellitus with concurrent acute coronary syndrome. Highlighted findings from current research underscore the inverse correlation between these biomarkers and the incidence of major adverse cardiovascular events, advocating their utility in risk stratification and clinical management of such patients.

INTRODUCTION

The intertwined relationship between type-2 diabetes mellitus (T2DM) and cardiovascular complications, particularly acute coronary syndrome (ACS), remains a formidable challenge in clinical management. The quest for reliable biomarkers that not only reflect disease activity but also predict long-term outcomes has led to the identification of serum bilirubin and γ-glutamyltranspeptidase (γ-GGT) as potential candidates. The study by Chen et al[1] stands at the intersection of this inquiry, providing evidence on the predictive value of these biomarkers in T2DM patients suffering from ACS. The study’s retrospective design encapsulated a substantial cohort (n = 271), delineating a significant negative correlation between serum bilirubin levels and major adverse cardiovascular events (MACEs), while γ-GGT levels painted a converse picture, being elevated in patients with a poorer prognosis.

Drawing parallels from Emiroglu et al[2], which included 219 patients with ACS, the findings suggested elevated serum glutamyltranspeptidase (GGT) levels irrespective of diabetes status, hinting at the enzyme’s role in atherosclerotic disease processes. Dalos et al[3], through a registry of 274 patients, reinforced the prognostic significance of γ-GGT, especially in heart failure with preserved ejection fraction, extending its relevance beyond coronary events. Ruttmann et al[4] further substantiate these observations in a cohort of 163944 individuals, associating higher γ-GGT levels with an increased risk of cardiovascular disease (CVD) mortality. Cho et al[5] and Baek et al[6] echo these findings, linking γ-GGT to all-cause and disease-specific mortality in a large-scale population study. These diverse studies converge on the notion that γ-GGT serves as an independent risk factor for myocardial infarction and cardiac death in patients with coronary artery disease, including those with T2DM. In contrast, serum bilirubin, an endogenous antioxidant, emerges as a protective factor against the onset of T2DM and subsequent cardiovascular complications. Its ability to counteract oxidative stress and inhibit lipid peroxidation presents a therapeutic avenue, potentially mitigating the progression of coronary artery disease, as suggested by the elevated levels found in healthier individuals across the referenced studies.

Recent research underscores the significance of serum bilirubin and γ-GGT as biomarkers in understanding the interplay between T2DM, ACS, and CVDs. The study by Chen et al[1] is pivotal in this regard, offering insights into the balance between oxidative stress and antioxidant systems within the body. It highlights serum bilirubin’s protective role and the correlational increase of γ-GGT levels with MACEs in T2DM patients with ACS. Raya-Cano et al[7] reviewed metabolic syndrome and transaminases: Systematic.

Complementing this, Fukui et al[8] demonstrate the inverse relationship between serum bilirubin concentrations and the degree of urinary albumin excretion and subclinical atherosclerosis in T2DM patients. Lin et al[9] delve into the genetic control of bilirubin concentrations and their protective effect against CVDs, including T2DM, metabolic syn-drome, and obesity. Furthermore, Passamonti et al[10] establish the endogenous presence of bilirubin in endothelial cells, vital for maintaining vascular health, thus extending the understanding of bilirubin’s antioxidative capacity.

The editorial concludes with a discussion on the implications of these findings for clinical practice. It underscores the importance of incorporating the measurement of serum bilirubin and γ-GGT levels in the routine assessment of T2DM patients, particularly those at risk of or presenting with ACS. It advocates for heightened surveillance and proactive management strategies in patients with deviations in these biomarkers, aiming to improve cardiovascular outcomes and reduce the burden of diabetes-related complications.

The insights gleaned from the referenced studies highlight the complex interplay of metabolic and cardiovascular systems, underpinned by molecular markers that could revolutionize prognostication and therapy in T2DM complicated by ACS. It is imperative for future research to further elucidate the mechanisms governing these relationships, enabling the refinement of predictive models and the development of targeted interventions that could curb the morbidity and mortality associated with these conditions. Chen et al[1] stands out by providing a balanced view of these mechanisms, suggesting potential pathways for targeted interventions and improved prognostic assessments in T2DM patients with ACS.

This synthesis of research not only corroborates the pivotal role of γ-GGT in cardiovascular pathology but also highlights the protective potential of antioxidants like bilirubin in the intricate landscape of diabetes and heart disease. Table 1 highlighted comparative analysis of studies on serum bilirubin and γ-GGT levels in CVDs based on their geography, cohort size.

Table 1 Comparative analysis of studies on serum bilirubin and γ-glutamyltransferase levels in cardiovascular diseases based on their geography, cohort size.

Ref.	Country	Sample size	Heart disease	Level of γ-GGT	Level of bilirubin	Citation journal	Year
Ruttmann et al[4]	Austria	163944	Various CVDs	Significantly associated with CVD mortality	-	Circulation	2005
Emiroglu et al[2]	Turkey	ACS: 219; Control: 51	Acute coronary syndrome	Higher in ACS patients	-	Acta Diabetol	2010
Fukui et al[8]	-	633	T2DM	-	Inversely correlated with albuminuria and subclinical atherosclerosis	Kidney Int	2008
Dalos et al[3]	-	HFpEF: 274	Heart failure with preserved ejection fraction	Independently associated with outcome	-	Sci Rep	2019
Passamonti et al[10]	-	-	-	-	Present in endothelial cells, antioxidative capacity	Meta Gene	2018
Lin et al[9]	-	-	-	-	Inversely associated with CVD and related diseases	Clinical Chemistry	2010
Cho et al[5]	Korea	9687066	General CVD	Increased levels associated with all-cause and CVD mortality	-	Sci Rep	2023
Baek et al[6]	Korea	1640127	Myocardial infarction, stroke, CVD	Cumulative high levels associated with increased CVD risk	-	Endocrinol Metab (Seoul)	2023
Chen et al[1]	China	T2DM + ACS: 96; T2DM: 85; ACS: 90	ACS	Increased in T2DM + ACS	Protective factor	World J Diabetes	2023

γ-GGT: γ-Glutamyltranspeptidase; CVDs: Cardiovascular diseases; ACS: Acute coronary syndrome; T2DM: Type-2 diabetes mellitus; HFpEF: Heart failure with preserved ejection fraction.

Limitations

While this editorial provides a comprehensive synthesis of current research on serum bilirubin and γ-GGT levels in the context of T2DM and ACS, several limitations should be acknowledged: (1) Scope of the studies reviewed: The editorial primarily focuses on studies that examine serum bilirubin and γ-GGT as biomarkers. While these studies are crucial, they represent a specific subset of the vast research on cardiovascular complications in T2DM and ACS. The exclusion of studies focusing on other biomarkers or mechanisms may limit the breadth of conclusions that can be drawn; (2) Variability in study designs: The studies reviewed encompass a range of designs, including retrospective analyses, cohort studies, and genetic linkage studies. The variability in methodologies and designs may introduce heterogeneity in the findings, making it challenging to draw universal conclusions; (3) Differences in patient populations: The studies involve diverse patient populations with varying demographics, disease severities, and treatment histories. These differences can affect the generalizability of the findings to broader populations; (4) Publication bias: The editorial primarily discusses published studies that report significant associations between the biomarkers and cardiovascular outcomes. This focus may overlook research with null or contradictory findings, potentially leading to publication bias; (5) Evolution of research: The field of cardiovascular research is rapidly evolving, with new studies and findings continually emerging. As such, the editorial represents a snapshot in time and may not include the very latest research developments; (6) Complexity of disease interactions: T2DM and ACS are complex diseases with multifactorial etiologies. The focus on specific biomarkers, while informative, does not fully capture the intricate pathophysiological interactions involved in these conditions; (7) Potential confounding factors: Although the studies attempt to control for confounding factors, there is always the potential for unmeasured variables that could influence the results. This is particularly relevant in observational studies where causality cannot be definitively established; and (8) Data interpretation and synthesis: The inter-pretation of data and synthesis of findings from multiple studies inherently involves subjective judgment. Efforts were made to present an unbiased view, but personal biases of the editorial team cannot be entirely excluded.

It could be summarized, while this editorial provides valuable insights into the roles of serum bilirubin and γ-GGT in T2DM and ACS, it is important to consider these limitations when interpreting the findings and applying them to clinical practice or future research.

CONCLUSION

The article by Chen et al[1] and other recent studies who estimated bilirubin levels provide an addition to the current understanding of the interplay between T2DM and ACS, particularly through the lens of serum biomarkers. These study distinguishes their selves in several key areas: (1) Specific patient population: It targets a cohort with both T2DM and ACS, offering focused insights into the complexities unique to this group, which is significant given the intricate interaction between these conditions; (2) Comparative approach: By comparing three distinct patient groups—T2DM + ACS, T2DM alone, and ACS alone—the study offers a comprehensive analysis of how biomarkers behave in various clinical scenarios; (3) Clinical outcomes correlation: The study’s examination of the correlation between serum bilirubin and γ-GGT levels with MACEs underscores the clinical relevance of these biomarkers in predicting patient outcomes; (4) Protective and risk factor analysis: Identifying serum bilirubin as a protective factor and γ-GGT as a risk factor for MACEs in T2DM + ACS patients, the study presents a nuanced understanding of these biomarkers’ roles; (5) Focus into oxidation and antioxidant balance: Chen et al’s work sheds light on the natural balance between oxidative stress and the antioxidant system in the human body[1]. Their findings regarding serum bilirubin, known for its potent antioxidant capacity, contribute to a better understanding of how the body’s natural defense mechanisms may be altered in health and disease, and particularly in the context of T2DM and ACS; and (6) Contribution to biomarker research: This article adds to the biomarker field by elucidating the prognostic significance of γ-GGT and serum bilirubin in a specific patient demographic, potentially guiding more tailored therapeutic strategies.

Chen et al’s study and recent studies are valuable contributions existing literature, reinforcing the importance of γ-GGT in cardiovascular risk assessment and unveiling the potential protective role of serum bilirubin[1]. This balanced view of oxidative and antioxidant systems in the human body, particularly in the context of T2DM and ACS, provides clinicians and researchers with critical insights that could lead to improved management and outcomes for these patients. The findings encourage further research into how these biomarkers can be utilized in clinical practice to enhance patient care.