Gamma-glutamyl transferase to high-density lipoprotein cholesterol ratio as a novel predictor of long-term ischemic heart disease risk in overweight men: a nationwide population-based study

1. Introduction

The global prevalence of obesity and overweight has reached epidemic proportions over the past few decades, fundamentally altering the landscape of public health and contributing to a corresponding surge in cardiovascular diseases (CVD) [1, 2]. In the male population, weight gain is typically characterized by the accumulation of visceral adipose tissue rather than subcutaneous fat. This android fat distribution pattern is metabolically active and is intrinsically linked to systemic chronic inflammation, insulin resistance, and the accelerated progression of atherosclerosis [3]. However, clinical observations have repeatedly demonstrated that cardiovascular risk is profoundly heterogeneous among individuals with identical body mass indices (BMI). This phenomenon highlights the significant limitations of traditional anthropometric measurements, such as BMI and waist circumference, which fail to distinguish between fat mass and lean muscle mass, nor can they accurately reflect the degree of ectopic fat deposition or subclinical metabolic dysregulation [4, 5]. Consequently, there is a critical need to identify robust, precise, and easily accessible metabolic markers that can better stratify cardiovascular risk, particularly among overweight men who may exhibit a deceptive “metabolically healthy” phenotype but remain at elevated risk for long-term adverse outcomes.

In recent years, gamma-glutamyl transferase (GGT) and high-density lipoprotein cholesterol (HDL-c) have garnered substantial attention beyond their traditional diagnostic roles. GGT is an enzyme located on the external surface of plasma membranes and plays a pivotal role in the metabolism of extracellular glutathione, the principal intracellular antioxidant [6]. Elevated serum GGT activity is no longer viewed merely as a biomarker of alcohol consumption or hepatobiliary dysfunction. Instead, it is now recognized as a sensitive and early indicator of systemic oxidative stress and endothelial dysfunction. High GGT levels actively participate in the atherogenic process by promoting the oxidation of low-density lipoprotein (LDL) within the arterial plaque, thereby promoting plaque instability [7, 8]. Furthermore, elevated GGT levels are strongly correlated with non-alcoholic fatty liver disease (NAFLD), a condition that independently increases the risk of cardiovascular morbidity [9].

Conversely, HDL-c is universally recognized for its cardioprotective properties. It is primarily responsible for reverse cholesterol transport, removing excess cholesterol from peripheral tissues and macrophages within arterial walls, and transporting it back to the liver for excretion [10]. Beyond lipid transport, HDL-c possesses potent anti-inflammatory, antioxidant, and antithrombotic functions. A reduction in HDL-c levels is a hallmark of atherogenic dyslipidemia and metabolic syndrome, serving as a powerful independent predictor of adverse cardiovascular events, especially among men [11].

The GGT/HDL-c ratio (GHR) has recently been proposed as a novel and integrative metabolic index. By mathematically combining these two parameters, the GHR simultaneously captures two critical, opposing pathophysiological pathways: the exacerbation of oxidative stress and hepatic steatosis (represented by GGT) and the depletion of cardioprotective and antioxidant capacity (represented by HDL-c) [12]. Emerging short-term and cross-sectional studies have indicated that the GHR is a valuable predictor of adverse cardiometabolic outcomes, including type 2 diabetes mellitus and coronary heart disease [13, 14]. The physiological rationale suggests that a high GHR reflects a highly atherogenic metabolic milieu, making it a potentially ideal surrogate marker for uncovering hidden cardiovascular risks in overweight individuals.

Despite the biological plausibility and promising preliminary data, the prognostic utility of the GHR for long-term clinical outcomes remains largely unexplored. Most existing literature relies on cross-sectional designs or short-term follow-ups and often focuses on general populations rather than specific high-risk subgroups [15]. To date, no large-scale, long-term longitudinal studies have adequately investigated whether baseline GHR can reliably predict cardiovascular morbidity and mortality specifically in overweight men over a span of several decades.

Therefore, the primary objective of this study is to evaluate the clinical significance of the GHR as a predictive metabolic marker for long-term cardiovascular risk in overweight men, utilizing data from a large-scale cohort with a 20-year follow-up period. We hypothesized that an elevated baseline GHR is independently and strongly associated with an increased risk of incident ischemic heart disease (IHD), even after adjusting for traditional risk factors such as age, smoking, hypertension, and baseline glycemic status. By leveraging two decades of longitudinal data, this work aims to clarify the metabolic mechanisms driving the divergence in cardiovascular outcomes among overweight men and to determine whether the GHR can serve as a simple, cost-effective screening tool for risk stratification in routine clinical practice.

2. Materials and methods

3. Results

3.2 Association between GGT/HDL-c ratio and IHD risk

During the follow-up period of up to 20 years, 7815 (6.3%) incident cases of IHD were identified. The cumulative incidence of IHD increased progressively across the GGT/HDL-c ratio quartiles (4.5%, 5.2%, 6.5%, and 9.0% for Q1 to Q4, respectively; p < 0.001). Fig. 1 illustrates the Kaplan-Meier curves for the cumulative incidence of IHD, showing a significantly higher risk in the highest quartile than in the reference group (Log-rank p < 0.001).

Fig. 1.Kaplan-Meier cumulative incidence plot of IHD by GGT/HDL-c ratio quartiles in overweight men over a follow-up period of up to 20 years. IHD, ischemic heart disease; HR, hazard ratio.

In the multivariable Cox proportional hazards model (Table 2), the GGT/HDL-c ratio was independently associated with an increased risk of IHD. After adjusting for age, lifestyle factors, BMI, and comorbidities (Model 4), the hazard ratio (HR) for Q4 compared with Q1 was 1.65 (95% CI 1.49–1.83).

Table 2.Hazard ratios and 95% confidence intervals for incident ischemic heart disease (IHD) according to GGT/HDL-c ratio (GHR) quartiles.

Variables	Q1 (Lowest)	Q2	Q3	Q4 (Highest)	p for trend	p-interaction
Total Population
	Model 1 (Unadjusted)	1.00 (Ref)	1.18 (1.06–1.32)	1.52 (1.37–1.68)	2.14 (1.93–2.37)	<0.001	-
	Model 2 (Age adjusted)	1.00 (Ref)	1.14 (1.02–1.27)	1.41 (1.27–1.56)	1.92 (1.73–2.12)	<0.001	-
	Model 3 (Lifestyle*)	1.00 (Ref)	1.11 (1.00–1.24)	1.35 (1.21–1.49)	1.78 (1.61–1.97)	<0.001	-
	Model 4 (Fully adjusted†)	1.00 (Ref)	1.09 (0.98–1.21)	1.28 (1.15–1.43)	1.65 (1.49–1.83)	<0.001	-
Subgroup Analysis (Model 4)
Physical Activity
	No (Inactive)	1.00 (Ref)	1.14 (1.01–1.28)	1.38 (1.22–1.56)	1.82 (1.61–2.06)	<0.001	<0.001
	Yes (Active)	1.00 (Ref)	1.04 (0.88–1.22)	1.16 (0.99–1.36)	1.42 (1.21–1.67)	0.001
*Model 3 adjusted for age, BMI, smoking, alcohol, and regular exercise. †Model 4 additionally adjusted for systolic BP, FBG, total cholesterol, and anti-hypertensive/lipid-lowering medication use. Ref, reference.

3.3 Subgroup analysis and interaction with physical activity

We observed a significant interaction between the GGT/HDL-c ratio and physical activity with respect to the risk of IHD (p for interaction < 0.001; Table 2). The association was more pronounced in the inactive group (Q4 HR: 1.82; 95% CI 1.61–2.06) than in the active group (Q4 HR: 1.42; 95% CI 1.21–1.67). Fig. 2 shows the restricted cubic spline analysis, which demonstrates a J-shaped relationship between the GGT/HDL-c ratio and IHD risk. Regular physical activity consistently mitigated the risk of IHD across the entire range of the GGT/HDL-c ratio compared with the inactive group.

Fig. 2.Restricted Cubic Spline Analysis of IHD Risk by GGT/HDL-c Ratio and Physical Activity. IHD, ischemic heart disease; CI, confidence interval; HR, hazard ratio; GGT, gamma-glutamyl transferase; HDL-c, high-density lipoprotein cholesterol.

4. Discussion

In this large-scale, nationwide population-based study of 124,044 overweight men, we demonstrated that the GGT/HDL-c ratio is a potent and independent predictor of long-term IHD risk. Over a follow-up period of up to 20 years, individuals in the highest GGT/HDL-c ratio quartile exhibited a 1.65-fold higher risk of incident IHD compared to those in the lowest quartile, even after rigorous adjustment for traditional cardiovascular risk factors. Notably, our study revealed a significant interaction between the GGT/HDL-c ratio and physical activity, suggesting that regular exercise may substantially mitigate the elevated cardiovascular risk associated with a high GGT/HDL-c ratio. Furthermore, the addition of this ratio to traditional risk models significantly improved risk reclassification, as evidenced by an NRI of 0.058.

The physiological significance of the GGT/HDL-c ratio lies in its ability to reflect the multifaceted nature of metabolic dysfunction and oxidative stress. Gamma-glutamyl transferase (GGT) is not merely a marker of hepatobiliary disease or alcohol consumption; it plays a crucial role in maintaining intracellular glutathione levels, the body’s primary antioxidant [16]. Elevated GGT levels are increasingly recognized as a surrogate marker for systemic oxidative stress and subclinical inflammation, both of which are central to the pathogenesis of atherosclerosis [17]. In contrast, HDL-c is well-known for its role in reverse cholesterol transport and its anti-inflammatory, anti-thrombotic, and antioxidant properties [18]. Therefore, the GGT/HDL-c ratio serves as a composite index that captures the imbalance between pro-oxidant burden and protective lipid profiles, providing a more comprehensive metabolic signature than either marker alone.

Our findings in overweight men are particularly relevant given the “obesity paradox” and the heterogeneity of metabolic health among individuals with a high BMI. While BMI is a common screening tool, it fails to distinguish between metabolically healthy and unhealthy obesity. The GGT/HDL-c ratio appears to bridge this gap by identifying those at the highest risk within the overweight population. Notably, a recent multi-cohort Korean study reported that the prognostic value of the GGT/HDL-c ratio for incident cardiovascular disease was more evident in women than in men [19]; our findings, drawn from a larger male-only cohort with two decades of follow-up and a coronary-specific endpoint, extend this literature by demonstrating a robust and graded association in overweight men [14]. The J-shaped relationship observed in our restricted cubic spline analysis (Fig. 2) suggests a threshold effect, where the risk of IHD increases sharply once the GGT/HDL-c ratio exceeds approximately 1.8. This “metabolic red line” could serve as a practical trigger for more aggressive clinical intervention in primary care settings.

This J-shaped pattern is consistent with a recent analysis of 50,462 U.S. adults in the National Health and Nutrition Examination Survey (NHANES), which similarly reported a J-shaped association between the GGT/HDL-c ratio and cardiovascular and all-cause mortality [15]. Biologically, the upturn in risk beyond this threshold may reflect a tipping point at which escalating oxidative stress and hepatic steatosis (reflected by elevated GGT levels) overwhelm the diminishing antioxidant and reverse-cholesterol-transport capacity of a depleted HDL pool, thereby accelerating endothelial dysfunction, LDL oxidation, and plaque instability. The relatively flat risk gradient below the threshold suggests that compensatory antioxidant reserves remain sufficient until the pro-oxidant burden crosses a critical level.

One of the most compelling findings of our study is the modulating effect of physical activity. The synergistic “double-hit” effect was evident: inactive men with a high GGT/HDL-c ratio faced nearly double the risk (HR 1.82) of IHD compared with the reference group, whereas this risk was significantly attenuated (HR 1.42) among those who engaged in regular physical activity. This interaction (p < 0.001) highlights the biological resilience afforded by exercise. Physical activity is known to enhance antioxidant defenses, improve insulin sensitivity, and promote more favorable HDL function, thereby counteracting the deleterious effects of high oxidative stress reflected by an elevated GGT/HDL-c ratio [20]. Clinically, this provides a powerful message for patient counseling: metabolic risk is not inevitable, and lifestyle modification remains a cornerstone of risk reduction even in high-risk individuals.

The clinical utility of a new biomarker is often judged by its incremental predictive value over established risk scores. Our results showed that adding the GGT/HDL-c ratio to a model containing age, BMI, smoking, and blood pressure significantly improved the C-index and, more importantly, the NRI (0.058). An NRI of 5.8% indicates that a substantial proportion of patients would be more accurately reclassified into appropriate risk categories using this ratio. In the context of our large cohort, this translates to a large number of individuals who could receive more timely and accurate preventive care. Given that both GGT and HDL-c are routinely measured in standard health check-ups at no additional cost, this ratio represents a cost-effective tool for refining risk stratification without the need for expensive genomic or imaging tests [21].

Several limitations of this study should be acknowledged. First, due to its observational nature, we cannot definitively establish a causal relationship. Second, although we adjusted for a wide range of confounders, the possibility of residual confounding by unmeasured factors remains. Third, the study population consisted exclusively of men; therefore, the findings may not be directly generalizable to women, who may exhibit different metabolic patterns. Fourth, the diagnosis of IHD was based on ICD-10 codes from the NHIS database, which, while widely used in epidemiological research, may be subject to misclassification. Fifth, we did not perform internal or external validation (e.g., bootstrapping or k-fold cross-validation) of the incremental predictive model; future studies should confirm the reproducibility of these estimates in independent cohorts. Finally, physical activity was assessed by self-report, which may be subject to recall and misclassification bias and could have attenuated or distorted the observed interaction.

Despite these limitations, the strengths of our study include the large sample size, the long-term follow-up duration, and the focus on a specific high-risk group (overweight men). To our knowledge, this is the first study to demonstrate the interaction between the GGT/HDL-c ratio and physical activity in a large-scale longitudinal cohort.

5. Conclusions

In conclusion, an elevated GGT/HDL-c ratio is a potent and independent predictor of long-term cardiovascular risk in overweight men, providing a simple and cost-effective tool for refining clinical risk stratification. Furthermore, our findings highlight that integrating this biomarker into routine assessments can effectively guide targeted lifestyle interventions, particularly emphasizing the critical role of regular physical activity in mitigating metabolic-related cardiovascular events.

Availability of data and materials

The data supporting the findings of this study are available from the National Health Insurance Service (NHIS) of Korea. However, restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of the NHIS.

Author contributions

UJ, EJ and HGK—conceptualization; resources; writing–review and editing; supervision; project administration. HKP, HYK and JYK—methodology; software and formal analysis. JYK, HYK and EJ—investigation; writing–original draft preparation. HYK and JYK—data curation; visualization. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Chonnam National University Hospital (CNUH-EXP-2025-082). All research procedures were conducted in strict accordance with the ethical principles for medical research involving human subjects, as outlined in the 1964 Declaration of Helsinki and its subsequent amendments.

Given the retrospective design of this study and the use of strictly anonymized, de-identified secondary clinical data provided by the National Health Insurance Service (NHIS) of Korea, the requirement for obtaining written informed consent from the participants was formally waived by the IRB of Chonnam National University Hospital.

Acknowledgment

Not applicable.

Funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2025-19252970) and supported by a grant HCRI-25037 of Chonnam National University Hospital Biomedical Research Institute.

Conflict of interest

The authors declare no conflict of interest.