Hyperlipidemia is a highly prevalent metabolic disorder and an established contributor to atherosclerotic cardiovascular disease (ASCVD) [1, 2]. In the United States, approximately 38% of adults have at least borderline high total cholesterol ($\ge$200 mg/dL), and 27.8% show increased levels of low-density lipoprotein cholesterol (LDL-C $\ge$130 mg/dL) [3]. Globally, elevated LDL-C was responsible for an estimated [4, 5] million deaths in 2020. This represents a 19% increase since 2010, thereby emphasizing the significant health burden of dyslipidaemia [3]. Notably, emerging evidence indicates that dyslipidemia is affecting younger populations with increasing frequency, potentially predisposing individuals to premature coronary events [2, 4, 5]. These trends highlight the need to improve risk stratification and preventive strategies in hyperlipidemic patients beyond traditional lipid measurements.

Mounting evidence implicates chronic low-grade inflammation in the pathogenesis of hyperlipidemia-related ASCVD [6, 7, 8]. It has been demonstrated that hyperlipidaemia can instigate an immune response that accelerates the formation of atherosclerotic plaque. For instance, neutrophils and other granulocytes have been observed to actively participate in the process of arterial inflammation and the progression of plaque [9, 10, 11]. Consistently, patients with cardiovascular disease often exhibit elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 [12], even when cholesterol levels are controlled. In this context, immune-cell indices have emerged as important markers of cardiovascular risk [13, 14, 15].

Systemic inflammatory indicators calculated based on a complete blood count (CBC), such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), can effectively reflect the association between these biomarkers and atherosclerotic lesions [16, 17]. NLR is characterized by its stability, easy accessibility, and low cost, and it can serve as an indicator reflecting the imbalance between innate and adaptive immunity [18]. Chen et al. [19] found that NLR levels above 3.42 were associated with 1.82-fold and 2.07-fold higher risks of all-cause and cardiovascular mortality, respectively, among individuals with pre-diabetes mellitus (DM) and DM. Furthermore, Hong et al. [20] also found a close association between an elevated NLR and adverse outcomes in patients with hypertension. However, limited evidence exists regarding the association between NLR and mortality risk in individuals with hyperlipidemia. Clarifying this relationship is essential for improving the clinical prognosis of these patients [21].

Notably, in metabolic conditions such as DM, interactions between inflammatory and insulin signaling pathways may jointly aggravate insulin resistance and endothelial dysfunction, thereby amplifying the contribution of inflammation to the progression of atherosclerosis and adverse cardiovascular outcomes [7, 22]. Given that patients with DM often have concurrent hyperlipidemia in primary care and clinical practice [23], particularly characterized by atherogenic dyslipidemia such as elevated triglyceride (TG) and small dense LDL particles that significantly raise cardiovascular risk [4, 23, 24], it is important to account for the potential influence of DM when evaluating the relationship between NLR and mortality risk in patients with hyperlipidemia.

In summary, this study, based on the National Health and Nutrition Examination Survey (NHANES) data, aims to evaluate the association of NLR with all-cause and cardiovascular mortality in patients with hyperlipidemia and to explore how this association varies across different glycemic status.

In this longitudinal cohort study, we found that NLR was positively associated with both all-cause and cardiovascular mortality among patients with hyperlipidemia, and this association was stronger under DM status. Additionally, the time-dependent ROC analysis showed that NLR had a greater advantage in predicting cardiovascular mortality than in predicting all-cause mortality.

A previous study has shown that among individuals with metabolic syndrome, higher NLR is associated with a significantly increased mortality risk, with each unit increase linked to a 14% higher all-cause mortality and the highest quartile demonstrating approximately 1.5-fold greater risk compared to the lowest [30]. Similarly, in patients with type 2 diabetes, elevated NLR independently predicted approximately two-fold higher all-cause mortality and nearly three-fold higher cardiovascular mortality when comparing the highest with the lowest NLR quartiles [31]. Even in the general population, extreme NLR elevations ($\ge$6) have been associated with approximately two-fold increased long-term mortality compared to normal NLR levels [32]. In this study, elevated NLR was positively associated with all-cause and cardiovascular mortality among patients with hyperlipidemia, consistent with evidence supporting NLR as a robust predictor of adverse metabolic diseases. Drechsler’s research suggests hyperlipidemia disrupts neutrophil homeostasis by altering their production, clearance, and mobilization, leading to elevated neutrophil counts in circulation and peripheral blood [21]. Within the NLR metric, neutrophils exert prominent pro-atherogenic effects, whereas lymphocytes have protective anti-atherogenic roles [33]. Neutrophils drive inflammation by initiating apoptosis and producing apoptotic debris, promoting lipid pool formation and thin-cap fibroatheroma plaque development, thus elevating cardiovascular risk [34]. Elevated lymphocyte counts reflect a balanced immune response and suppression of inflammatory pathways, thus protecting arterial vessels from the onset and progression of atherosclerosis [35]. The NLR partially represents the balance between pro- and anti-atherogenic processes, potentially explaining the heightened risk of cardiovascular events and mortality in hyperlipidemic patients. The strong association between high NLR and mortality is biologically plausible given that NLR integrates two critical dimensions of the immune response. Specifically, neutrophils are key effectors of innate inflammation, while lymphocytes (especially T-cells) orchestrate adaptive immunity; thus, an elevated NLR signifies excessive neutrophil-driven inflammation coupled with relative lymphopenia [36, 37]. This imbalance can lead to a state of chronic, low-grade inflammation alongside impaired immune regulation.

Interestingly, the results of subgroup analysis and interaction testing indicated an interaction between NLR and DM, which subsequently influenced the strength of the association between NLR and outcome events. Further analysis suggested that the joint effect of high NLR (Q4) and DM can synergistically increase the risk of all-cause and cardiovascular mortality among patients with hyperlipidemia. Both high lipid levels and hyperglycemia are known to trigger the release of inflammatory cytokines like interleukin-6 and tumor necrosis factor-$\alpha$ [38]. These cytokines not only induce oxidative stress and endothelial dysfunction (thereby accelerating atherosclerosis) [39, 40], but also interfere with insulin signaling, promoting insulin resistance. Therefore, when hyperlipidemia and DM coexist, the pro-atherogenic effects of inflammation and the degree of insulin resistance become further aggravated. Indeed, a clinical study has noted that NLR correlates positively with insulin resistance in diabetics [41], supporting a vicious cycle whereby inflammation and impaired metabolism fuel one another. Additionally, the specific interaction between inflammatory signaling pathways and insulin signaling pathways leads to enhanced metabolic insulin resistance and endothelial dysfunction [7, 22], exacerbating endothelial damage and consequently increasing the risk of target organ damage and mortality [42]. This may partially explain why higher NLR patients with DM exhibited a significantly increased risk of death.

This study has several limitations. First, due to the observational nature of the NHANES dataset, a causal relationship between elevated NLR levels and mortality outcomes cannot be definitively established. Second, although extensive covariate adjustments were performed, the possibility of residual confounding from unmeasured or unknown factors, such as dietary patterns, physical activity, and additional inflammatory biomarkers, cannot be completely ruled out. Third, because NLR was measured only once at baseline, we were unable to assess the potential impact of longitudinal changes in NLR on mortality risk. Fourth, the lack of continuous hs-CRP measurements in the NHANES database precluded a direct comparison between NLR and hs-CRP in evaluating mortality risk among patients with hyperlipidemia. Finally, this study primarily focused on the association between NLR and mortality rather than its clinical application in risk prediction; therefore, further studies are warranted to evaluate the clinical utility of NLR in clinical settings.

In summary, our study found that elevated NLR was positively associated with both all-cause and cardiovascular mortality among patients with hyperlipidemia. Importantly, the observed interaction between NLR and DM highlights a clinically significant subgroup at particularly elevated risk, suggesting that dysregulated glucose metabolism may amplify the adverse effects of chronic inflammation. These findings provide compelling evidence to consider NLR as a practical and effective clinical biomarker, underscoring the potential utility of integrated therapeutic approaches targeting inflammation and glucose metabolism to mitigate mortality risk in individuals with hyperlipidemia.

Data for this study are freely available on the NHANES website at https://www.cdc.gov/nchs/nhanes/.

QZ: Conceptualization, Writing-original draft, Formal analysis. YC: Conceptualization, Writing-original draft, Methodology, Data curation, Formal analysis, Visualization, Writing-review & editing. HJ: Data curation, Visualization, Writing-review & editing. XZ: Conceptualization, Writing-review & editing, Supervision, Funding acquisition. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was carried out in accordance with the guidelines of the Declaration of Helsinki. The protocol for NHANES was approved by the National Center for Health Statistics and Ethics Review Board. All participants provided written informed consent. As this is a secondary analysis, no further ethics approval was required for the present analysis.

We express our gratitude to all individuals and organizations who contributed to the NHANES project.

This study was supported by the National Natural Science Foundation of China (No. 82370438).

The authors declare no conflict of interest. YC and XZ are serving as Guest Editors of this journal. We declare that YC and XZ had no involvement in the peer review of this article and had no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Brian Tomlinson.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM46797.