Abstract
Background
The association between low-density lipoprotein cholesterol (LDL-C) levels and clinical outcomes in patients with liver cirrhosis (LC) remains unclear. In this study, we aimed to investigate the association between LDL-C levels and cardiovascular events, along with all-cause death in patients with LC, using a nationwide database.
Materials and methods
This retrospective cohort study included 303,988 patients with LC identified from the Korean National Health Insurance Service database who underwent health examinations between 2009 and 2017. Patients were categorised into six LDL-C groups (<70, 70–99, 100–129, 130–159, 160–189, and ≥190 mg/dL). The primary outcomes were (1) a composite of myocardial infarction and ischaemic stroke and (2) all-cause death.
Results
Higher LDL-C levels were associated with a dose-dependent increase in the risk of cardiovascular events. Compared to the reference group (<70 mg/dL), patients with LDL-C ≥ 190 mg/dL had a 1.77-fold higher risk of a composite outcome and a 2.96-fold increased risk of myocardial infarction. Conversely, a U-shaped relationship was observed between LDL-C levels and all-cause death, with the lowest risk observed in the 130–159 mg/dL group. These findings were consistent across the subgroups with compensated or decompensated LC and various underlying aetiologies.
Conclusion
This large-scale nationwide study demonstrated that elevated LDL-C levels are significantly associated with an increased risk of cardiovascular events in patients with LC, while both low and high LDL-C levels are associated with a higher risk of all-cause death. These findings highlight the need for individualised lipid management strategies in this high-risk population.
Keywords: Cardiovascular disease, low-density lipoprotein cholesterol, liver cirrhosis, outcome, statin
Key Messages
Elevated LDL-C levels are significantly associated with an increased risk of myocardial infarction and ischaemic stroke in patients with liver cirrhosis, in a dose-dependent manner.
A U-shaped relationship was observed between LDL-C levels and all-cause death, with the lowest risk seen in the 130–159 mg/dL group.
These associations were consistent across subgroups stratified by cirrhosis status and aetiologies, underscoring the need for tailored lipid management in this high-risk population.
Introduction
Low-density lipoprotein cholesterol (LDL-C) is the key contributing factor to atherosclerotic cardiovascular diseases (ASCVD), including myocardial infarction (MI) and ischaemic stroke [1]. Given its pivotal role in ASCVD pathogenesis, intensive lowering of LDL-C levels is particularly important in patients with established ASCVD [2]. Additionally, elevated LDL-C levels are associated with an increased risk of ASCVD events in the general population, necessitating lipid-lowering therapy tailored to the individual's ASCVD risk [3,4]. However, observational studies have identified a phenomenon referred to as the 'cholesterol paradox', which tends to be more pronounced in vulnerable populations, particularly older adults [5]. An inverse association is observed between LDL-C levels and all-cause death, while the association between LDL-C levels and cardiovascular events remains unclear in this population [6–8]. These findings suggest that the interplay between LDL-C levels and clinical outcomes is complex and varies across different patient groups.
Patients with liver cirrhosis (LC) are at an increased risk of ASCVD [9]. Although cirrhosis was previously considered protective against atherosclerotic disease, current evidence indicates that coronary artery disease may be more prevalent among patients with LC than in the general population [10,11]. Increased cardiovascular risk is accompanied by distinct metabolic alterations in patients with LC. Due to impaired liver function and malnutrition, patients with LC exhibit abnormal lipid profiles characterised by declining serum cholesterol (including LDL-C) levels as the disease progresses; studies have consistently shown lower cholesterol levels in patients with LC compared to healthy individuals and an inverse correlation with disease severity [12]. Although the association between LDL-C levels and disease severity is well established, the impact of LDL-C on clinical outcomes, particularly cardiovascular events and mortality in patients with LC, remains poorly understood [13,14].
Statins remain the cornerstone of lipid-lowering therapy and are recommended for cardiovascular risk reduction in patients with compensated LC [15,16], due to their favourable safety profile and potential to delay decompensation and reduce liver-related complications [17,18]. However, the extent to which they influence cardiovascular events and whether these benefits are directly mediated by cholesterol-lowering remains uncertain [19,20]. These gaps underscore the need for further studies to clarify the role of LDL-C in predicting adverse outcomes in this unique population. Moreover, the aetiology of cirrhosis, such as alcohol-related liver disease, viral hepatitis, and non-alcoholic steatohepatitis (NASH), may differentially influence the cardiovascular risk through distinct metabolic profiles, inflammatory responses and patterns of comorbidity [21]. However, the role of LDL-C in clinical outcomes has not been thoroughly investigated across these subtypes.
Therefore, in this study, we aimed to investigate the association between LDL-C levels and clinical outcomes, including cardiovascular events and all-cause death in patients with LC, using comprehensive data from the Korean National Health Insurance Service (NHIS). Additionally, subgroup analyses were conducted according to cirrhosis status (compensated vs. decompensated) and underlying aetiology to provide insights into future strategies for optimising lipid management in this highly vulnerable population.
Material and methods
Study population
This study included a nationwide, longitudinal cohort of patients with LC who underwent health examinations between 2009 and 2017. From the NHIS database, we initially identified 431,741 patients aged ≥20 years who were diagnosed with LC and subsequently participated in the National Health Screening Program. LC was defined as either a hospital admission listing ICD-10 codes K702, K703, K717, K74, K761, K765, or K766 as the primary or first secondary diagnosis or at least two outpatient visits [22]. The first health screening examination during the study period was used as the index date. Exclusion criteria included the following: (1) a history of myocardial infarction or ischaemic stroke (n = 11,593), (2) prior liver transplantation (n = 4,054), (3) triglyceride levels ≥ 400 mg/dL (n = 15,085), (4) missing variables (n = 59,009), and (5) statin use before the index date (n = 38,012). Finally, 303,988 patients were included in the study cohort. Patients were stratified into six groups according to their baseline LDL-C levels: <70 mg/dL (n = 46,006), 70–99 mg/dL (n = 99,633), 100–129 mg/dL (n = 97,042), 130–159 mg/dL (n = 45,111), 160–189 mg/dL (n = 12,641), and ≥190 mg/dL (n = 3,555). The selection process is illustrated in Figure 1. For subgroup analyses, patients were further categorised according to their cirrhosis status and aetiology. Decompensated LC was defined as the presence of LC accompanied by diagnostic codes indicating complications (I85.0, I86.4, I98.3, K72, K72.1, K72.9, K76.7, R17, or R18). Patients who did not meet these criteria were classified as having compensated LC. To explore aetiologic differences, the underlying cause of LC was identified based on diagnostic codes recorded before or concurrent with the initial LC diagnosis. The aetiology was classified as alcohol-related (F10.1, K70.1, K70.2, K70.3, K70.4, or K70.9), hepatitis B virus (B18.0, B18.1, or Z22.51), hepatitis C virus (B18.2 or Z22.52), or non-alcoholic fatty liver disease (NAFLD)/NASH (K75.8 or K76.0, in the absence of other identifiable aetiologies). These classification criteria are based on previously validated algorithms from published studies (Supplemental Table S1) [22–24].
Figure 1.
Flowchart illustrating the study population. LDL, low-density lipoprotein; MI, myocardial infarction.
Data collection
This nationwide study was conducted using data extracted from the Korean NHIS database, which compiles nationwide health information for nearly the entire South Korean population. The NHIS database incorporates patient demographics, medical claims (including the International Classification of Diseases, Tenth Revision [ICD-10] diagnostic codes, procedure codes, and prescription records), and dates and causes of death. Moreover, it integrates biannual health screening (National Health Screening Program) data encompassing self-reported lifestyle factors, physical measurements, and laboratory test results. Detailed characteristics of the NHIS database have been described previously [25].
Baseline data were obtained from index health examinations. Demographic information included age, sex, and socioeconomic status, which were classified into quartiles based on household income. Lifestyle factors were determined using standardised questionnaires, obtaining data on smoking status (never, past, current), frequency of alcohol consumption (none, 1–2 times/week, ≥3 times/week), and exercise frequency (none, 1–2 times/week, 3–4 times/week, ≥5 times/week). Blood pressure (systolic and diastolic) was measured according to standardised protocols. Anthropometric data included body mass index (BMI), categorised as <18.5, 18.5–22.9, 23.0–24.9, or ≥25 kg/m2. Laboratory data included fasting glucose, lipid profiles, haemoglobin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. LDL-C levels were calculated using the Friedewald equation [26]. The estimated glomerular filtration rate (eGFR) was derived using the Modification of Diet in Renal Disease equation [27]. A medical history of hypertension and diabetes mellitus was identified using diagnostic codes and prescription records. The comorbidity burden was estimated using the modified Charlson Comorbidity Index [28]. The use of medications, including statins, other lipid-lowering agents, antihypertensive drugs, antidiabetic drugs, and antiplatelet agents, was recorded. Supplemental Table S1 provides detailed definitions of the study population, comorbidities, medication use, and outcomes, including the diagnostic codes and procedures used for classification.
Outcomes
The co-primary outcomes of this study were (1) composite cardiovascular outcomes (composite of major adverse cardiovascular events, including myocardial infarction and ischaemic stroke) and (2) all-cause death. Each component of the composite cardiovascular outcome was evaluated separately as a secondary outcome. Mortality data, including the cause and date of death, were obtained from official death records. Myocardial infarction (ICD-10 codes I21–I22) and ischaemic stroke (ICD-10 codes I63–I64) were defined in hospitalised patients as that confirmed by relevant imaging or interventional procedures. Participants were followed up from their index date until the occurrence of an outcome event or until the end of the study period (31 December 2022), whichever occurred first.
Ethical consideration
This study was approved by the Institutional Review Board of Hanyang University Guri Hospital (approval no. GURI 2024-06-028). The requirement for informed consent was waived owing to the retrospective nature of the study and use of de-identified data from the Korean NHIS database. This study complied with the ethical guidelines of the Declaration of Helsinki.
Statistical analysis
Continuous variables are expressed as means ± standard deviations and were compared across groups using a one-way analysis of variance, while categorical variables are reported as numbers (percentages) and were evaluated using chi-square tests.
To illustrate event-free survival across different LDL-C categories, Kaplan–Meier curves were generated, and the log-rank test was used for comparisons. Incidence rates (per 10,000 person-years) were calculated for each outcome. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between LDL-C levels and each outcome, with the lowest LDL-C category (<70 mg/dL) serving as a reference. To address potential confounders, three progressively adjusted models were constructed. Model 1 was adjusted for age and sex; Model 2 additionally included BMI, smoking status, alcohol consumption, exercise frequency, and household income; and Model 3 further incorporated haemoglobin, eGFR, Charlson Comorbidity Index, hypertension, diabetes mellitus, and antiplatelet agent use. Restricted cubic spline analyses were performed to explore the potential nonlinear relationships between continuous LDL-C levels and clinical outcomes, incorporating the covariates used in Model 3. Additionally, subgroup analyses were performed to evaluate the consistency of the association between cirrhosis status (compensated vs. decompensated), categories of LC aetiology, and cause of death (liver-related vs. nonliver-related death). Finally, for competing risk analyses of cardiovascular outcomes and cause-specific mortality, subdistribution hazard ratios and 95% CIs were estimated using the Fine and Gray model.
All data processing and statistical analyses were performed using SAS Enterprise (version 7.1; SAS Institute, Cary, NC, USA) and R (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria). Finally, a two-sided p value <0.05 was considered statistically significant.
Results
Baseline characteristics
Table 1 provides the baseline characteristics of the 303,988 patients with LC stratified by LDL-C category. The largest subgroup had LDL-C levels of 70–99 mg/dL, whereas the smallest subgroup had LDL-C ≥ 190 mg/dL. All variables differed significantly across the categories (p < 0.001). Patients with LDL-C levels <70 mg/dL were older, more frequently male, had higher rates of hypertension and diabetes mellitus, had lowest haemoglobin levels, had poorer liver function test results, and had the highest prevalence of current smoking and frequent alcohol consumption (≥3 times/week). The group with the highest LDL-C (≥190 mg/dL) levels and that with LDL-C 70–99 mg/dL exhibited relatively unfavourable profiles, although less pronounced than those observed in the <70 mg/dL group. They had lower haemoglobin levels, abnormal liver function test results, higher rates of current smoking and frequent alcohol consumption, lower frequency of exercise, lower household incomes, and greater comorbidity burdens. In contrast, patients in the mid-range LDL-C category (100–189 mg/dL) demonstrated more favourable characteristics, including higher haemoglobin levels, milder liver enzyme elevations, lower rates of current smoking and frequent alcohol consumption, comorbidities, and higher household incomes.
Table 1.
Baseline characteristics.
| Low-density lipoprotein cholesterol level (mg/dL) |
|||||||
|---|---|---|---|---|---|---|---|
| <70 | 70–99 | 100–129 | 130–159 | 160–189 | ≥190 | p value | |
| Total patients (N = 303,988) | (n = 46,006) | (n = 99,633) | (n = 97,042) | (n = 45,111) | (n = 12,641) | (n = 3,555) | |
| Age, years | 58.1 ± 11.2 | 56.6 ± 11.8 | 55.9 ± 11.5 | 55.6 ± 11.3 | 55.6 ± 11.1 | 55.7 ± 11.1 | <0.001 |
| Sex, n (%) | <0.001 | ||||||
| Male | 35,135 (76.4) | 69,052 (69.3) | 64,286 (66.2) | 28,165 (62.4) | 7,474 (59.1) | 2,030 (57.1) | |
| Female | 10,871 (23.6) | 30,581 (30.7) | 32,756 (33.8) | 16,946 (37.6) | 5,167 (40.9) | 1,525 (42.9) | |
| Blood pressure, mmHg | |||||||
| SBP | 124.7 ± 16.3 | 123.7 ± 15.5 | 124.1 ± 15.1 | 124.7 ± 15.1 | 125.2 ± 15.2 | 126.1 ± 16.0 | <0.001 |
| DBP | 76.3 ± 10.7 | 76.1 ± 10.2 | 76.7 ± 10.0 | 77.3 ± 10.0 | 77.7 ± 10.0 | 78.1 ± 10.4 | <0.001 |
| Fasting glucose, mg/dL | 113.0 ± 44.5 | 106.4 ± 35.2 | 104.4 ± 30.7 | 104.1 ± 29.8 | 104.9 ± 30.6 | 107.9 ± 36.1 | <0.001 |
| Haemoglobin, g/dL | 13.2 ± 2.1 | 13.8 ± 1.8 | 14.1 ± 1.6 | 14.2 ± 1.6 | 14.2 ± 1.6 | 14.1 ± 1.7 | <0.001 |
| Aspartate aminotransferase, U/L | 56.8 ± 75.9 | 42.5 ± 47.2 | 37.8 ± 39.7 | 36.5 ± 39.1 | 38.4 ± 41.7 | 48.9 ± 65.8 | <0.001 |
| Alanine aminotransferase, U/L | 38.7 ± 53.4 | 35.4 ± 45.7 | 34.3 ± 41.9 | 34.7 ± 39.0 | 36.3 ± 34.9 | 42.8 ± 53.7 | <0.001 |
| Gamma-glutamyl transferase, U/L | 142.4 ± 196.2 | 87.1 ± 138.8 | 73.3 ± 121.0 | 71.3 ± 119.2 | 80.4 ± 138.5 | 123.4 ± 207.0 | <0.001 |
| Estimated glomerular filtration rate, mL/min/1.73 m2 | 86.4 ± 24.8 | 85.9 ± 22.5 | 85.2 ± 21.2 | 84.8 ± 20.9 | 84.2 ± 20.6 | 83.8 ± 22.0 | <0.001 |
| Smoking, n (%) | <0.001 | ||||||
| Never | 20,400 (44.3) | 50,757 (50.9) | 51,049 (52.6) | 24,269 (53.8) | 6,972 (55.2) | 1,896 (53.3) | |
| Past | 9,433 (20.5) | 21,947 (22.0) | 21,381 (22.0) | 9,404 (20.8) | 2,382 (18.8) | 631 (17.7) | |
| Current | 16,173 (35.2) | 26,929 (27.0) | 24,612 (25.4) | 11,438 (25.4) | 3,287 (26.0) | 1,028 (28.9) | |
| Alcohol consumption, times/week | <0.001 | ||||||
| 0 | 24,712 (53.7) | 63,921 (64.2) | 63,153 (65.1) | 29,065 (64.4) | 8,239 (65.2) | 2,320 (65.3) | |
| 1–2 | 8,067 (17.5) | 19,243 (19.3) | 20,401 (21.0) | 10,060 (22.3) | 2,695 (21.3) | 664 (18.7) | |
| ≥3 | 13,227 (28.8) | 16,469 (16.5) | 13,488 (13.9) | 5,986 (13.3) | 1,707 (13.5) | 571 (16.1) | |
| Exercise, times/week | <0.001 | ||||||
| 0 | 26,464 (57.5) | 52,568 (52.8) | 48,775 (50.3) | 22,813 (50.6) | 6,590 (52.1) | 1,971 (55.4) | |
| 1–2 | 8,866 (19.3) | 21,614 (21.7) | 22,862 (23.6) | 10,736 (23.8) | 2,909 (23.0) | 761 (21.4) | |
| 3–4 | 5,577 (12.1) | 13,629 (13.7) | 14,230 (14.7) | 6,639 (14.7) | 1,782 (14.1) | 484 (13.6) | |
| ≥5 | 5,099 (11.1) | 11,822 (11.9) | 11,175 (11.5) | 4,923 (10.9) | 1,360 (10.8) | 339 (9.5) | |
| Body mass index, kg/m2 | <0.001 | ||||||
| <18.5 | 2,924 (6.4) | 4,143 (4.2) | 2,691 (2.8) | 949 (2.1) | 267 (2.1) | 70 (2.0) | |
| 18.5–22.9 | 20,125 (43.7) | 38,862 (39.0) | 33,428 (34.4) | 13,731 (30.4) | 3,740 (29.6) | 1,046 (29.4) | |
| 23–24.9 | 10,405 (22.6) | 24,436 (24.5) | 24,595 (25.3) | 11,673 (25.9) | 3,174 (25.1) | 926 (26.0) | |
| ≥25 | 12,552 (27.3) | 32,192 (32.3) | 36,328 (37.4) | 18,758 (41.6) | 5,460 (43.2) | 1,513 (42.6) | |
| Household income, quartiles | <0.001 | ||||||
| First | 12,543 (27.3) | 23,729 (23.8) | 21,468 (22.1) | 9,884 (21.9) | 2,877 (22.8) | 923 (26.0) | |
| Second | 9,526 (20.7) | 19,318 (19.4) | 18,028 (18.6) | 8,195 (18.2) | 2,442 (19.3) | 702 (19.7) | |
| Third | 11,164 (24.3) | 24,535 (24.6) | 23,670 (24.4) | 10,929 (24.2) | 3,001 (23.7) | 862 (24.2) | |
| Fourth | 12,773 (27.8) | 32,051 (32.2) | 33,876 (34.9) | 16,103 (35.7) | 4,321 (34.2) | 1,068 (30.0) | |
| Charlson Comorbidity Index | <0.001 | ||||||
| ≤1 | 13,118 (28.5) | 34,624 (34.8) | 38,128 (39.3) | 19,175 (42.5) | 5,446 (43.1) | 1,547 (43.5) | |
| 2 | 8,821 (19.2) | 20,433 (20.5) | 21,255 (21.9) | 10,020 (22.2) | 2,856 (22.6) | 737 (20.7) | |
| 3 | 6,705 (14.6) | 14,943 (15.0) | 14,415 (14.9) | 6,491 (14.4) | 1,823 (14.4) | 482 (13.6) | |
| 4 | 5,757 (12.5) | 11,033 (11.1) | 9,641 (9.9) | 4,074 (9.0) | 1,086 (8.6) | 312 (8.8) | |
| ≥5 | 11,605 (25.2) | 18,600 (18.7) | 13,603 (14.0) | 5,351 (11.9) | 1,430 (11.3) | 477 (13.4) | |
| Hypertension | 16,922 (36.8) | 32,497 (32.6) | 29,274 (30.2) | 13,030 (28.9) | 3,466 (27.4) | 1,024 (28.8) | <0.001 |
| Diabetes mellitus | 10,821 (23.5) | 17,893 (18.0) | 13,944 (14.4) | 5,246 (11.6) | 1,291 (10.2) | 423 (11.9) | <0.001 |
| Antiplatelet agent use | 5,772 (12.5) | 11,638 (11.7) | 11,150 (11.5) | 5,027 (11.1) | 1,440 (11.4) | 438 (12.3) | <0.001 |
DBP, diastolic blood pressure; SBP, systolic blood pressure.
Clinical outcomes according to LDL-C categories
Figure 2 displays the Kaplan–Meier curves for each outcome across the LDL-C categories. For the composite cardiovascular outcome (Figure 2A), event-free survival was the poorest in patients with LDL-C ≥ 190 mg/dL, followed by those with 160–189 mg/dL and <70 mg/dL. In contrast, all-cause death was highest among individuals with LDL-C < 70 mg/dL, followed by those with 70–99 mg/dL and ≥190 mg/dL (Figure 2B). The risk of myocardial infarction displayed a clear dose-dependent trend, with the highest incidence observed at LDL-C ≥ 190 mg/dL and the lowest at LDL-C < 70 mg/dL (Figure 2C). Finally, for ischaemic stroke, those with LDL-C ≥ 190 mg/dL had the poorest survival, followed by LDL-C < 70 mg/dL and LDL-C 160–189 mg/dL (Figure 2D).
Figure 2.
Kaplan–Meier survival curves for clinical outcomes stratified by LDL-C categories (A) composite cardiovascular outcome (myocardial infarction and ischaemic stroke), (B) all-cause death, (C) myocardial infarction, and (D) ischaemic stroke. LDL-C, low-density lipoprotein cholesterol.
Table 2 represents the HRs from Cox proportional hazards regression models across the LDL-C categories for clinical outcomes, with sequential adjustments in the three models to account for potential confounders. The fully adjusted models showed a clear dose-dependent relationship between increasing LDL-C levels and composite cardiovascular outcomes (comprising myocardial infarction and ischaemic stroke). Compared to the reference group (<70 mg/dL), all categories of LDL-C > 70–99 mg/dL showed a statistically significant increase in risk, culminating in a 1.77-fold higher hazard (HR: 1.77, 95% CI: 1.49–2.10, p < 0.001) for those with LDL-C ≥ 190 mg/dL. Myocardial infarction and ischaemic stroke individually followed a similar pattern, with the ≥190 mg/dL group displaying a 2.96-fold higher risk of myocardial infarction (HR: 2.96, 95% CI: 2.07–4.22, p < 0.001) and a 1.52-fold higher risk of ischaemic stroke (HR: 1.52, 95% CI: 1.25–1.86, p < 0.001), compared to the < 70 mg/dL group. In contrast, the other co-primary endpoint (all-cause death) showed a U-shaped association. Patients with LDL-C levels in the 130–159 mg/dL range experienced the lowest risk (HR: 0.57, 95% CI: 0.55–0.58, p < 0.001), while those with LDL-C < 70 mg/dL had the highest risk (reference group), followed by the 70–99 mg/dL (HR: 0.80, 95% CI: 0.78–0.81, p < 0.001) and the ≥ 190 mg/dL groups (HR: 0.76, 95% CI: 0.71–0.82, p < 0.001).
Table 2.
Risk of clinical outcomes according to LDL-C categories.
| Total patients (N = 303,988) |
Model 1 |
Model 2 |
Model 3 |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LDL-C categories | Participants | Events | Incidence rate per 10,000 PY | HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |
| Composite cardiovascular outcome (Myocardial infarction or ischaemic stroke) | ||||||||||
| <70 | 46,006 | 1,298 | 0.102 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 99,633 | 2,897 | 0.092 | 1.00 (0.93–1.06) | 0.873 | 1.05 (0.99–1.13) | 0.116 | 1.08 (1.01–1.15) | 0.023 | |
| 100–129 | 97,042 | 3,095 | 0.096 | 1.09 (1.02–1.16) | 0.010 | 1.17 (1.09–1.25) | <0.001 | 1.22 (1.14–1.31) | <0.001 | |
| 130–159 | 45,111 | 1,516 | 0.100 | 1.19 (1.10–1.28) | <0.001 | 1.26 (1.16–1.35) | <0.001 | 1.34 (1.24–1.45) | <0.001 | |
| 160–189 | 12,641 | 481 | 0.115 | 1.41 (1.27–1.57) | <0.001 | 1.48 (1.33–1.64) | <0.001 | 1.59 (1.43–1.77) | <0.001 | |
| ≥190 | 3,555 | 146 | 0.130 | 1.66 (1.40–1.97) | <0.001 | 1.67 (1.40–1.98) | <0.001 | 1.77 (1.49–2.10) | <0.001 | |
| All-cause death | ||||||||||
| <70 | 46,006 | 20,408 | 1.582 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 99,633 | 29,419 | 0.927 | 0.64 (0.63–0.65) | <0.001 | 0.68 (0.67–0.69) | <0.001 | 0.80 (0.78–0.81) | <0.001 | |
| 100–129 | 97,042 | 20,154 | 0.617 | 0.45 (0.44–0.46) | <0.001 | 0.49 (0.48–0.50) | <0.001 | 0.64 (0.62–0.65) | <0.001 | |
| 130–159 | 45,111 | 7,591 | 0.491 | 0.37 (0.36–0.38) | <0.001 | 0.41 (0.40–0.42) | <0.001 | 0.57 (0.55–0.58) | <0.001 | |
| 160–189 | 12,641 | 2,117 | 0.495 | 0.39 (0.37–0.41) | <0.001 | 0.42 (0.40–0.44) | <0.001 | 0.59 (0.56–0.62) | <0.001 | |
| ≥190 | 3,555 | 768 | 0.671 | 0.54 (0.50–0.58) | <0.001 | 0.56 (0.52–0.60) | <0.001 | 0.76 (0.71–0.82) | <0.001 | |
| Myocardial infarction | ||||||||||
| <70 | 46,006 | 190 | 0.015 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 99,633 | 588 | 0.019 | 1.39 (1.18–1.64) | <0.001 | 1.41 (1.20–1.66) | <0.001 | 1.45 (1.23–1.71) | <0.001 | |
| 100–129 | 97,042 | 759 | 0.023 | 1.84 (1.57–2.16) | <0.001 | 1.85 (1.57–2.17) | <0.001 | 1.94 (1.65–2.28) | <0.001 | |
| 130–159 | 45,111 | 469 | 0.030 | 2.55 (2.16–3.02) | <0.001 | 2.52 (2.12–2.99) | <0.001 | 2.69 (2.26–3.20) | <0.001 | |
| 160–189 | 12,641 | 147 | 0.035 | 3.04 (2.45–3.77) | <0.001 | 2.95 (2.37–3.66) | <0.001 | 3.19 (2.56–3.97) | <0.001 | |
| ≥190 | 3,555 | 37 | 0.032 | 2.98 (2.09–4.24) | <0.001 | 2.79 (1.96–3.97) | <0.001 | 2.96 (2.07–4.22) | <0.001 | |
| Ischaemic stroke | ||||||||||
| <70 | 46,006 | 1,122 | 0.088 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 99,633 | 2,346 | 0.075 | 0.93 (0.86–1.00) | 0.035 | 1.00 (0.93–1.07) | 0.907 | 1.02 (0.95–1.10) | 0.595 | |
| 100–129 | 97,042 | 2,376 | 0.074 | 0.96 (0.89–1.03) | 0.254 | 1.05 (0.97–1.12) | 0.228 | 1.10 (1.02–1.18) | 0.013 | |
| 130–159 | 45,111 | 1,072 | 0.070 | 0.96 (0.88–1.04) | 0.290 | 1.03 (0.95–1.13) | 0.457 | 1.10 (1.01–1.20) | 0.025 | |
| 160–189 | 12,641 | 339 | 0.080 | 1.13 (1.00–1.28) | 0.051 | 1.21 (1.07–1.36) | 0.003 | 1.30 (1.15–1.47) | <0.001 | |
| ≥190 | 3,555 | 109 | 0.097 | 1.40 (1.15–1.70) | <0.001 | 1.44 (1.18–1.75) | <0.001 | 1.52 (1.25–1.86) | <0.001 | |
CI, confidence interval; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; PY, person-years; Ref, reference.
Model 1: adjusted for age and sex.
Model 2: adjusted for age, sex, body mass index, smoking status, alcohol consumption, exercise, and household income.
Model 3: adjusted for age, sex, body mass index, smoking status, alcohol consumption, exercise, household income, haemoglobin level, estimated glomerular filtration rate, Charlson Comorbidity Index, hypertension, diabetes mellitus, and antiplatelet agent use.
Figure 3 represents restricted cubic spline analyses showing a continuous association between LDL-C levels and each clinical outcome. The composite cardiovascular outcomes (Figure 3A), myocardial infarction (Figure 3C), and ischaemic stroke (Figure 3D) showed a progressive increase in risk with increasing LDL-C levels, with myocardial infarction demonstrating the most pronounced relationship. In contrast, all-cause death exhibited a U-shaped curve, indicating that very low and very high LDL-C levels are associated with higher mortality, whereas patients with intermediate levels had the lowest risk (Figure 3B).
Figure 3.
Restricted cubic spline curves illustrating consistent association between LDL-C levels and clinical outcomes. (A) composite cardiovascular outcome (myocardial infarction and ischaemic stroke), (B) all-cause death, (C) myocardial infarction, and (D) ischaemic stroke. LDL, low-density lipoprotein; CI, confidence interval.
Subgroup and sensitivity analysis
Subgroup analyses were conducted to evaluate the consistency of the association between cirrhosis status and etiologic subtypes. When stratified by cirrhosis status, both the compensated and decompensated LC groups showed trends consistent with the overall population. The associations between higher LDL-C levels and cardiovascular outcomes were maintained or more pronounced in the decompensated group, while the U-shaped relationship with all-cause death was less evident in patients with decompensated LC, particularly at very high LDL-C levels (Table 3; Supplementary Table S2). In aetiology-based analyses, alcohol-related LC, hepatitis B, hepatitis C, and NAFLD/NASH subgroups demonstrated a broadly similar pattern of LDL-C association with cardiovascular events and all-cause death, with some variation in the magnitude of the risk estimates (Supplementary Tables S3–S6). To further investigate cause-specific mortality, we conducted additional subgroup analyses for liver-related and nonliver-related death (Supplemental Table S7). Both outcomes demonstrated increased risks at the lower and higher LDL-C levels, showing a pattern similar to the U-shaped association observed for all-cause death. However, liver-related death exhibited a more prominent reverse J-shaped pattern, with the lowest risk observed in the LDL-C category of 160–189 mg/dL.
Table 3.
Risk of clinical outcomes according to LDL-C categories in patients with compensated liver cirrhosis.
| Total patients (N = 223,270) |
Model 1 |
Model 2 |
Model 3 |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LDL-C categories | Participants | Events | Incidence rate per 10,000 PY | HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |
| Composite cardiovascular outcome (Myocardial infarction or ischaemic stroke) | ||||||||||
| <70 | 25,968 | 852 | 0.104 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 70,295 | 2,071 | 0.087 | 0.93 (0.86–1.01) | 0.081 | 0.99 (0.91–1.07) | 0.764 | 1.02 (0.94–1.10) | 0.701 | |
| 100–129 | 76,681 | 2,410 | 0.090 | 1.02 (0.95–1.11) | 0.552 | 1.09 (1.01–1.19) | 0.026 | 1.15 (1.06–1.25) | <0.001 | |
| 130–159 | 37,109 | 1,248 | 0.096 | 1.14 (1.05–1.25) | 0.003 | 1.21 (1.10–1.32) | <0.001 | 1.29 (1.18–1.41) | <0.001 | |
| 160–189 | 10,453 | 399 | 0.111 | 1.36 (1.21–1.54) | <0.001 | 1.42 (1.26–1.60) | <0.001 | 1.53 (1.36–1.73) | <0.001 | |
| ≥190 | 2,764 | 113 | 0.121 | 1.53 (1.25–1.86) | <0.001 | 1.53 (1.25–1.86) | <0.001 | 1.62 (1.33–1.98) | <0.001 | |
| All-cause death | ||||||||||
| <70 | 25,968 | 7,311 | 0.880 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 70,295 | 12,906 | 0.534 | 0.68 (0.66–0.70) | <0.001 | 0.74 (0.72–0.76) | <0.001 | 0.81 (0.78–0.83) | <0.001 | |
| 100–129 | 76,681 | 10,543 | 0.390 | 0.52 (0.51–0.54) | <0.001 | 0.59 (0.57–0.61) | <0.001 | 0.68 (0.66–0.71) | <0.001 | |
| 130–159 | 37,109 | 4,347 | 0.330 | 0.46 (0.45–0.48) | <0.001 | 0.53 (0.51–0.55) | <0.001 | 0.64 (0.62–0.67) | <0.001 | |
| 160–189 | 10,453 | 1,244 | 0.340 | 0.49 (0.46–0.52) | <0.001 | 0.55 (0.52–0.58) | <0.001 | 0.68 (0.64–0.72) | <0.001 | |
| ≥190 | 2,764 | 381 | 0.401 | 0.59 (0.54–0.66) | <0.001 | 0.63 (0.57–0.70) | <0.001 | 0.76 (0.69–0.85) | <0.001 | |
| Myocardial infarction | ||||||||||
| <70 | 25,968 | 131 | 0.016 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 70,295 | 445 | 0.018 | 1.31 (1.08–1.60) | 0.006 | 1.33 (1.09–1.62) | 0.004 | 1.38 (1.13–1.68) | <0.001 | |
| 100–129 | 76,681 | 606 | 0.022 | 1.69 (1.40–2.04) | <0.001 | 1.69 (1.40–2.05) | <0.001 | 1.79 (1.48–2.17) | <0.001 | |
| 130–159 | 37,109 | 398 | 0.030 | 2.43 (1.99–2.96) | <0.001 | 2.39 (1.95–2.91) | <0.001 | 2.56 (2.10–3.14) | <0.001 | |
| 160–189 | 10,453 | 122 | 0.034 | 2.81 (2.19–3.60) | <0.001 | 2.71 (2.11–3.48) | <0.001 | 2.96 (2.31–3.81) | <0.001 | |
| ≥190 | 2,764 | 30 | 0.032 | 2.77 (1.86–4.12) | <0.001 | 2.58 (1.73–3.84) | <0.001 | 2.76 (1.85–4.11) | <0.001 | |
| Ischaemic stroke | ||||||||||
| <70 | 25,968 | 730 | 0.089 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||||
| 70–99 | 70,295 | 1,654 | 0.069 | 0.86 (0.79–0.94) | 0.001 | 0.93 (0.85–1.02) | 0.104 | 0.96 (0.87–1.04) | 0.304 | |
| 100–129 | 76,681 | 1,836 | 0.069 | 0.90 (0.83–0.99) | 0.021 | 0.99 (0.90–1.08) | 0.744 | 1.03 (0.95–1.13) | 0.460 | |
| 130–159 | 37,109 | 873 | 0.067 | 0.92 (0.83–1.01) | 0.094 | 0.99 (0.90–1.10) | 0.876 | 1.06 (0.96–1.18) | 0.249 | |
| 160–189 | 10,453 | 281 | 0.078 | 1.09 (0.95–1.26) | 0.203 | 1.16 (1.01–1.34) | 0.033 | 1.26 (1.09–1.45) | 0.001 | |
| ≥190 | 2,764 | 83 | 0.088 | 1.27 (1.01–1.60) | 0.038 | 1.30 (1.04–1.64) | 0.023 | 1.39 (1.10–1.74) | 0.005 | |
CI, confidence interval; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; PY, person-years; Ref, reference.
Model 1: adjusted for age and sex.
Model 2: adjusted for age, sex, body mass index, smoking status, alcohol consumption, exercise, and household income.
Model 3: adjusted for age, sex, body mass index, smoking status, alcohol consumption, exercise, household income, haemoglobin level, estimated glomerular filtration rate, Charlson Comorbidity Index, hypertension, diabetes mellitus, and antiplatelet agent use.
Additionally, sensitivity analyses using a competing risk approach were performed, in which liver-related death was treated as a competing event for cardiovascular outcomes (composite outcome, myocardial infarction, and ischemic stroke), and liver-related and nonliver-related deaths were considered competing events for each other (Supplemental Table S8). The competing risk analysis demonstrated dose-dependent associations between higher LDL-C levels and increased risk of cardiovascular outcomes, consistent with the findings from the Cox proportional hazards models. For liver-related death, a similar reverse J-shaped association was observed, whereas the U-shaped association for nonliver-related death was attenuated.
Discussion
In this large-scale nationwide longitudinal cohort study of patients with LC, we investigated the association between LDL-C levels and clinical outcomes using data from the Korean NHIS. The key findings can be summarised as follows: (1) higher LDL-C levels were linked to a dose-dependent increase in the risk of a composite cardiovascular outcome (myocardial infarction and ischaemic stroke), with particularly pronounced effects on myocardial infarction; (2) in contrast, the risk of all-cause death was lowest among individuals with LDL-C levels in the 130–159 mg/dL range, whereas LDL-C levels below this range were associated with a progressively higher risk, indicating an inverted J-shaped or U-shaped relationship; and (3) these associations were consistently observed in both compensated and decompensated LC and across subgroups stratified by underlying aetiology, supporting the robustness of the findings across clinically diverse patient populations. These key findings broaden our understanding of lipid-related risk stratification in this unique population, demonstrating a dose-dependent association between LDL-C and cardiovascular events while revealing a 'cholesterol paradox' for all-cause death.
Cirrhosis was previously thought to protect against ASCVD because of factors such as coagulopathy, thrombocytopenia, and lower cholesterol levels [11,29]. However, recent studies have challenged this assumption by highlighting the substantial prevalence of coronary artery disease in patients with LC [30,31], although managing dyslipidaemia in such patients remains a challenge. Patients with LC exhibit distinct alterations in lipid metabolism, often presenting with declining LDL-C levels as the liver function deteriorates. Furthermore, although statins are the cornerstone of lipid-lowering therapy, concerns regarding hepatotoxicity have historically limited their use in LC [32]. Although studies have demonstrated its safety and potential benefits in this population, these benefits may extend beyond lowering LDL-C alone, suggesting a more complex interplay between lipid metabolism and cardiovascular risk in LC [33]. Given the growing recognition of ASCVD risk in patients with LC and the uncertainties surrounding lipid management, large-scale population-based studies are required to clarify the role of LDL-C in predicting cardiovascular risk in this unique population.
Extensive epidemiological and interventional studies have demonstrated that lowering LDL-C levels reduces the incidence of myocardial infarction and stroke, confirming its causal role in atherosclerosis [34]. Consistent with these findings, we observed a significant dose-dependent increase in cardiovascular risk with higher LDL-C levels. Individuals with LDL-C ≥ 190 mg/dL had a 1.77-fold higher risk of composite cardiovascular outcome than those with LDL-C < 70 mg/dL, with a threefold increased risk of myocardial infarction. These results emphasise the importance of LDL-C as a key determinant of cardiovascular risk, even in patients with LC. However, in contrast to the cardiovascular outcomes, all-cause death exhibited a U-shaped association with LDL-C levels, with both low and high LDL-C levels associated with increased mortality. This pattern has been reported previously, particularly in older individuals [5,6,35]. One widely discussed explanation is reverse causation, in which low LDL-C levels reflect poor health status [36]. Supporting this hypothesis, the patients in the lowest LDL-C group in our study exhibited the most unfavourable baseline characteristics, including older age, poorer liver function, and a higher burden of comorbidities. However, even after adjusting for these confounding factors, the U-shaped association persisted, suggesting the involvement of additional mechanisms. Furthermore, subgroup analyses stratified by cirrhosis status (compensated vs. decompensated) and aetiology consistently demonstrated similar patterns of association, supporting the robustness and generalisability of our findings across clinically relevant subpopulations. The relationship between LDL-C level and cardiovascular risk remained significant even among patients with decompensated cirrhosis, whereas a U-shaped association with all-cause death was more evident in those with compensated disease. In addition, aetiology-based subgroup analyses revealed consistent associations between LDL-C levels and clinical outcomes in patients with alcohol-related cirrhosis, viral hepatitis, and NAFLD/NASH. Although the overall trends were similar, certain variation in the effect size was observed, suggesting that metabolic heterogeneity across aetiological subtypes may influence lipid-associated risks. Further research is warranted to clarify the differential impact of LDL-C on LC aetiology.
The mechanisms underlying the association between LDL-C and cardiovascular events and all-cause death in patients with LC remain poorly understood. However, several mechanisms can potentially explain our findings. The causal role of LDL-C in ASCVD is well established, with extensive evidence supporting its contribution to atherogenesis via endothelial dysfunction and oxidative stress [37]. Beyond the traditional pathophysiology, chronic systemic inflammation associated with LC may further increase the risk of ASCVD [38]. Moreover, the aetiology of cirrhosis may influence ASCVD risk, as conditions such as NASH, viral hepatitis, and primary biliary cholangitis are linked to increased cardiovascular risk through metabolic dysfunction, systemic inflammation, and dysregulated lipid metabolism [21].
The U-shaped relationship between LDL-C level and all-cause death observed in our study has been widely reported in various populations, with an ongoing debate regarding its interpretation [35,36]. Prior research suggests that this association may differ based on primary vs. secondary prevention status, baseline ASCVD risk, and statin use [35,39,40]. This pattern is more pronounced in vulnerable populations, such as older individuals and individuals with chronic illnesses, where lower LDL-C levels may reflect frailty [5,41]. Given the central role of the liver in lipid metabolism, lower LDL-C levels in patients with LC may indicate hepatic dysfunction and poor overall health, contributing to the observed U-shaped association [42]. Further studies are needed to elucidate the complex interplay between LDL-C levels, cardiovascular risk, and long-term survival in this high-risk population.
Our findings have several practical implications for managing lipid levels and cardiovascular risk in patients with LC. First, traditional cardiovascular prevention strategies should not be overlooked. Most lipid-related studies in LC have primarily focused on the safety of statin therapy, whereas large-scale, long-term epidemiologic data on the relationship between LDL-C levels and ASCVD remain limited [15–20]. Although statins exert pleiotropic effects beyond lipid lowering [33], understanding the direct role of LDL-C in ASCVD risk in patients with LC is essential. Moreover, with the increasing availability of non-statin lipid-lowering therapies, achieving optimal LDL-C targets may become more feasible. Given the heterogeneity of LC, a better epidemiological understanding of the relationship between LDL-C levels and clinical outcomes could provide a foundation for personalised lipid management strategies in this high-risk population. We observed that patients with LC and very low LDL-C levels require careful monitoring, as they are at a high risk of mortality, regardless of whether this reflects reverse causality. However, individuals with LDL-C ≥ 160 mg/dL exhibited a significantly elevated ASCVD risk and an increased risk of all-cause death, highlighting their need for intensive lifestyle modifications and statin therapy. Further research is required to establish optimal LDL-C targets and develop individualised lipid-lowering strategies for patients with LC.
This study has certain limitations. First, as an observational study, a causal relationship between LDL-C levels and clinical outcomes could not be definitively established. Although we adjusted for multiple confounders, residual confounding may still be present, particularly due to unmeasured factors such as nutritional status and statin initiation or adherence during follow-up. In addition, the possibility of reverse causality cannot be excluded. Second, important clinical indicators of disease severity such as the Model for End-Stage Liver Disease score and Child–Pugh classification were not available in our dataset. These factors may influence both LDL-C levels and clinical outcomes. To address this, we performed subgroup analyses based on cirrhosis status (compensated vs. decompensated). However, this binary classification may not fully capture the biological gradient of disease severity, and this limitation should be considered when interpreting the results. Third, our reliance on the NHIS database introduced potential issues related to misclassification and data accuracy. LC diagnoses are identified using administrative claims and diagnostic codes rather than histological or imaging confirmation, which may lead to misclassification. Fourth, although the aetiology of LC was included in the subgroup analyses, residual confounding factors related to disease severity or overlapping aetiologies may persist. Fifth, health examination data included LDL-C levels assessed at a single time point without serial measurements to capture longitudinal changes. Finally, although this study used a nationwide database covering nearly the entire Korean population, caution is needed when generalising the findings to other populations. Future prospective studies are needed to validate these findings and further refine lipid management strategies in patients with LC.
Conclusion
This large-scale nationwide cohort study demonstrated that higher LDL-C levels are significantly associated with an increased risk of cardiovascular events in patients with LC. In contrast, a U-shaped relationship was observed between LDL-C level and all-cause death. These findings highlight the complex role of LDL-C in this unique population and emphasise the need for individualised lipid management strategies. Future studies are warranted to investigate optimal LDL-C targets and the potential benefits of lipid-lowering interventions in patients with LC.
Supplementary Material
Acknowledgement
None.
Disclosure statement
The authors report no conflict of interest.
Data availability statement
The data that support the findings of this study are available from the Korean NHIS. Restrictions apply to the availability of these data, which were used under license for the current study (NHIS-2024-10-1-023). Data are available from the NHIS (https://nhiss.nhis.or.kr) upon reasonable request and with permission of the NHIS.
References
- 1.Vaduganathan M, Mensah GA, Turco JV, et al. The global burden of cardiovascular diseases and risk. J Am Coll Cardiol. 2022;80(25):2361–2371. doi: 10.1016/j.jacc.2022.11.005. [DOI] [PubMed] [Google Scholar]
- 2.Virani SS, Smith SC, Jr., Stone NJ, et al. Secondary prevention for atherosclerotic cardiovascular disease: comparing recent US and European guidelines on dyslipidemia. Circulation. 2020;141(14):1121–1123. doi: 10.1161/CIRCULATIONAHA.119.044282. [DOI] [PubMed] [Google Scholar]
- 3.Mach F, Baigent C, Catapano AL, et al. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2019;41(1):111–188. [DOI] [PubMed] [Google Scholar]
- 4.Arnett DK, Blumenthal RS, Albert MA, et al. ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Circulation. 2019;140(11):e596–e646. 2019. doi: 10.1161/CIR.0000000000000678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lee YB, Koo M, Noh E, et al. Myocardial infarction, stroke, and all-cause mortality according to low-density lipoprotein cholesterol level in the elderly, a nationwide study. Diabetes Metab J. 2022;46(5):722–732. doi: 10.4093/dmj.2021.0225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401. doi: 10.1136/bmjopen-2015-010401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Maihofer AX, Shadyab AH, Wild RA, et al. Associations between serum levels of cholesterol and survival to age 90 in postmenopausal women. J Am Geriatr Soc. 2020;68(2):288–296. doi: 10.1111/jgs.16306. [DOI] [PubMed] [Google Scholar]
- 8.Nanna MG, Navar AM, Wojdyla D, et al. The association between low-density lipoprotein cholesterol and incident atherosclerotic cardiovascular disease in older adults: results from the National Institutes of Health pooled cohorts. J Am Geriatr Soc. 2019;67(12):2560–2567. doi: 10.1111/jgs.16123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lin SY, Lin CL, Lin CC, et al. Risk of acute coronary syndrome and peripheral arterial disease in chronic liver disease and cirrhosis: a nationwide population-based study. Atherosclerosis. 2018;270:154–159. doi: 10.1016/j.atherosclerosis.2018.01.047. [DOI] [PubMed] [Google Scholar]
- 10.Kalaitzakis E, Rosengren A, Skommevik T, et al. Coronary artery disease in patients with liver cirrhosis. Dig Dis Sci. 2010;55(2):467–475. doi: 10.1007/s10620-009-0738-z. [DOI] [PubMed] [Google Scholar]
- 11.An J, Shim JH, Kim SO, et al. Prevalence and prediction of coronary artery disease in patients with liver cirrhosis: a registry-based matched case–control study. Circulation. 2014;130(16):1353–1362. doi: 10.1161/CIRCULATIONAHA.114.009278. [DOI] [PubMed] [Google Scholar]
- 12.Ghadir MR, Riahin AA, Havaspour A, et al. The relationship between lipid profile and severity of liver damage in cirrhotic patients. Hepat Mon. 2010;10(4):285–288. [PMC free article] [PubMed] [Google Scholar]
- 13.Janičko M, Veselíny E, Leško D, et al. Serum cholesterol is a significant and independent mortality predictor in liver cirrhosis patients. Ann Hepatol. 2013;12(4):581–587. doi: 10.1016/S1665-2681(19)31342-0. [DOI] [PubMed] [Google Scholar]
- 14.Gananandan K, Trebicka J, Claria J, et al. P68 low-density lipoprotein can predict hospital readmissions and outcomes following acute decompensation of cirrhosis. Gut. 2024; 73( Suppl 3):A54–A55. doi: 10.1136/gutjnl-2024-BASL.77. [DOI] [Google Scholar]
- 15.European Association for the Study of the Liver (EASL) . European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492–542. doi: 10.1016/j.jhep.2024.04.031. [DOI] [PubMed] [Google Scholar]
- 16.Speliotes EK, Balakrishnan M, Friedman LS, et al. Treatment of dyslipidemia in common liver diseases. Clin Gastroenterol Hepatol. 2018;16(8):1189–1196. doi: 10.1016/j.cgh.2018.04.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kumar S, Grace ND, Qamar AA.. Statin use in patients with cirrhosis: a retrospective cohort study. Dig Dis Sci. 2014;59(8):1958–1965. doi: 10.1007/s10620-014-3179-2. [DOI] [PubMed] [Google Scholar]
- 18.Mohanty A, Tate JP, Garcia-Tsao G.. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis. Gastroenterology. 2016;150(2):430–440.e1. doi: 10.1053/j.gastro.2015.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Sung S, Al-Karaghouli M, Kalainy S, et al. A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis. BMC Gastroenterol. 2021;21(1):120. doi: 10.1186/s12876-021-01704-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kreidieh M, Hamadi R, Alsheikh M, et al. Statin use in patients with chronic liver disease and cirrhosis: current evidence and future directions. Gastroenterology Res. 2022;15(1):1–12. doi: 10.14740/gr1498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gîrleanu I, Trifan A, Huiban L, et al. Ischemic heart disease and liver cirrhosis: adding insult to injury. Life (Basel). 2022;12(7):1036. doi: 10.3390/life12071036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Jang SY, Rou WS, Kim SH, et al. Association between new-onset liver cirrhosis and suicide risk in South Korea: a nationwide cohort study. Clin Mol Hepatol. 2021;27(2):283–294. doi: 10.3350/cmh.2020.0227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Hayward KL, Johnson AL, Horsfall LU, et al. Detecting non-alcoholic fatty liver disease and risk factors in health databases: accuracy and limitations of the ICD-10-AM. BMJ Open Gastroenterol. 2021;8(1):e000572. doi: 10.1136/bmjgast-2020-000572. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Hagström H, Adams LA, Allen AM, et al. Administrative coding in electronic health care record-based research of NAFLD: an expert panel consensus statement. Hepatology. 2021;74(1):474–482. doi: 10.1002/hep.31726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kyoung DS, Kim HS.. Understanding and utilizing claim data from the Korean National Health Insurance Service (NHIS) and health insurance review and assessment (HIRA) database for research. J Lipid Atheroscler. 2022;11(2):103–110. doi: 10.12997/jla.2022.11.2.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Friedewald WT, Levy RI, Fredrickson DS.. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502. doi: 10.1093/clinchem/18.6.499. [DOI] [PubMed] [Google Scholar]
- 27.Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247–254. doi: 10.7326/0003-4819-145-4-200608150-00004. [DOI] [PubMed] [Google Scholar]
- 28.Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. doi: 10.1016/0021-9681(87)90171-8. [DOI] [PubMed] [Google Scholar]
- 29.Howell WL, Manion WC.. The low incidence of myocardial infarction in patients with portal cirrhosis of the liver: a review of 639 cases of cirrhosis of the liver from 17,731 autopsies. Am Heart J. 1960;60(3):341–344. doi: 10.1016/0002-8703(60)90192-7. [DOI] [PubMed] [Google Scholar]
- 30.Gu C, Dong L, Chai L, et al. Risk of coronary artery disease in patients with liver cirrhosis: a systematic review and meta-analysis. J Clin Transl Hepatol. 2025;13(2):93–104. doi: 10.14218/JCTH.2024.00226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Kazankov K, Munk K, Øvrehus KA, et al. High burden of coronary atherosclerosis in patients with cirrhosis. Eur J Clin Invest. 2017;47(8):565–573. doi: 10.1111/eci.12777. [DOI] [PubMed] [Google Scholar]
- 32.Schulze J, Glass X.. Statin hepatotoxicity and the dilemma of causality in rare hepatic adverse drug reactions. J Hepatol. 2012;57(3):702–703. author reply 703. doi: 10.1016/j.jhep.2012.03.010. [DOI] [PubMed] [Google Scholar]
- 33.Pose E, Napoleone L, Amin A, et al. Safety of two different doses of simvastatin plus Rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2020;5(1):31–41. doi: 10.1016/S2468-1253(19)30320-6. [DOI] [PubMed] [Google Scholar]
- 34.Mhaimeed O, Burney ZA, Schott SL, et al. The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: lower for longer is better. Am J Prev Cardiol. 2024;18:100649. doi: 10.1016/j.ajpc.2024.100649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Johannesen CDL, Langsted A, Mortensen MB, et al. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. BMJ. 2020;371:m4266. doi: 10.1136/bmj.m4266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Liu Y, Liu F, Zhang L, et al. Association between low density lipoprotein cholesterol and all-cause mortality: results from the NHANES 1999–2014. Sci Rep. 2021;11(1):22111. doi: 10.1038/s41598-021-01738-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313–2330. doi: 10.1093/eurheartj/ehz962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Kronsten VT, Shawcross DL.. Clinical implications of inflammation in patients with cirrhosis. Am J Gastroenterol. 2025;120(1):65–74. doi: 10.14309/ajg.0000000000003056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Park CS, Yang HM, Han K, et al. J-shaped association between LDL cholesterol and cardiovascular events: a longitudinal primary prevention cohort of over 2.4 million people nationwide. J Adv Res. 2024;58:139–147. doi: 10.1016/j.jare.2023.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Chen L, Chen S, Bai X, et al. Low-density lipoprotein cholesterol, cardiovascular disease risk, and mortality in China. JAMA Netw Open. 2024;7(7):e2422558. doi: 10.1001/jamanetworkopen.2024.22558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011;70(3):482–487. doi: 10.1136/ard.2010.135871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Chrostek L, Supronowicz L, Panasiuk A, et al. The effect of the severity of liver cirrhosis on the level of lipids and lipoproteins. Clin Exp Med. 2014;14(4):417–421. doi: 10.1007/s10238-013-0262-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the Korean NHIS. Restrictions apply to the availability of these data, which were used under license for the current study (NHIS-2024-10-1-023). Data are available from the NHIS (https://nhiss.nhis.or.kr) upon reasonable request and with permission of the NHIS.