# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=en - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20241113160439+05'30' - ModDate=D:20260725013647-07'00' - Producer=MPS - Title=LIPPINCOTT WILLIAMS AND WILKINS - xmp:modifydate=2026-07-25T01:36:47-07:00 - xmp:createdate=2024-11-13T16:04:39+05:30 - xmp:metadatadate=2026-07-25T01:36:47-07:00 - pdf:producer=MPS - dc:format=application/pdf - dc:title=LIPPINCOTT WILLIAMS AND WILKINS - xmpmm:documentid=uuid:53ddf60d-3a0c-47f3-b087-76cd5c529de0 - xmpmm:instanceid=uuid:d527d0f2-ba09-4965-b00a-230a54515151 - adhocwf:state=1 - adhocwf:version=1.1 - pdfuaid:part=1 - pdfaextension:schemas=http://ns.adobe.com/pdf/1.3/pdfAdobe PDF SchemainternalA name object indicating whether the document has been modified to include trapping informationTrappedTexthttp://ns.adobe.com/xap/1.0/mm/xmpMMXMP Media Management SchemainternalUUID based identifier for specific incarnation of a documentInstanceIDURIinternalThe common identifier for all versions and renditions of a document.OriginalDocumentIDURIhttp://www.aiim.org/pdfua/ns/id/pdfuaidPDF/UA ID SchemainternalPart of PDF/UA standardpartInteger ## Contents ### Page 1 Received: 19 February 2026 | Accepted: 15 June 2026 DOI: 10.1097/HC9.0000000000001013 ![Figure]() # O R I G I N A L A R T I C L E # The risk of cardiovascular events in metabolic dysfunction–associated steatotic liver disease according to fibrosis stage and diabetes status: A cohort study Jaehong Jeong 1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea , 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea , 3Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea Jung Pyo Hong,,, 4Department of Internal Medicine, Gyeongsang National University College of Medicine, Jinju, Republic of Korea Dong Yun Kim,,Jae Seung Lee,, Mi Na Kim,, Jeong Eun Song 5Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea Hyun Chin Cho Beom Kyung Kim,, Jun Yong Park,,Do Young Kim,, Sang Hoon Ahn,, Hye Won Lee,,Seung Up Kim,, Abbreviations: AASLD, American Association for the Study of Liver Diseases; ACC, American College of Cardiology; AGA, American Gastroenterological Association; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; EASL, European Association for the Study of the Liver; FIB-4, fibrosis-4; HbA1c, hemoglobin A1c; ICD, International Classification of Diseases; KASL, Korean Association for the Study of the Liver; LS, liver stiffness; MASLD, metabolic dysfunction–associated steatotic liver disease; NIT, noninvasive test; sHR, subdistribution hazard ratio; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; VCTE, vibration-controlled transient elastography. Jaehong Jeong and Jung Pyo Hong have equally contributed to this work.Hye Won Lee and Seung Up Kim contributed equally as co-corresponding authors. Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website,. This is an open access article distributed under the terms of the, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2026 The Author(s). Published by Wolters Kluwer Health, LLC. on behalf of the American Association for the Study of Liver Diseases. CorrespondenceSeung Up Kim, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul 03722, Republic of Korea. Email: ## Abstract ## Background: Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality in metabolic dysfunction–associated steatotic liver disease (MASLD). We investigated whether fibrosis severity assessed using guideline-recommended noninvasive liver fibrosis pathways was associated with incident ASCVD across different glycemic states. ## Methods: This retrospective cohort study included subjects with MASLD. Fibrosis severity was classified using the Korean Association for the Study of the Liver/European Association for the Study of the Liver (KASL/EASL) and American Gastroenterological Association (AGA) sequential pathways, based on fibrosis-4 followed by vibration-controlled transient elastography. Incident ASCVD was analyzed using Fine-Gray subdistribution hazard models, with death treated as a competing event. ## Results: Among 6519 subjects with MASLD who had both fibrosis-4 and vibration-controlled transient elastography data, 3243 had normoglycemia, 2369 had prediabetes, and 907 had diabetes; 3221 were included in the survival analysis cohort. Baseline 10-year ASCVD risk increased with wor-sening glycemic status. In the longitudinal analysis, the association between ### Page 2 fibrosis severity and incident ASCVD differed by glycemic status. In patients with prediabetes, the highest fibrosis tier was associated with higher incident ASCVD risk (adjusted subdistribution hazard ratio: 2.62, p = 0.024). This association was also more apparent in younger individuals. In patients with diabetes, 5-year cumulative ASCVD incidence was high across fibrosis tiers (15.2%–18.5%), without a significant increase by fibrosis severity. ## Conclusions: Higher liver fibrosis severity assessed by noninvasive tests was associated with incident ASCVD outcomes in selected MASLD sub-groups, particularly patients with prediabetes and younger individuals. Fibrosis assessment may help identify patients who warrant closer car-diometabolic evaluation when interpreted alongside established ASCVD risk prediction tools. ## Keywords: atherosclerotic cardiovascular disease, diabetes mellitus, fibrosis-4 index, liver fibrosis, metabolic dysfunction–associated steatotic liver disease, vibration-controlled transient elastography ## INTRODUCTION Metabolic dysfunction–associated steatotic liver disease (MASLD) is now understood not as a liver-centric condition but as the hepatic manifestation of a systemic metabolic disorder, representing the most prevalent chronic liver disease worldwide. Central to this paradigm shift is evidence that atherosclerotic cardio-vascular disease (ASCVD) is the leading cause of death in individuals with MASLD, a risk that is independent of traditional cardiovascular risk factors and is significantly driven by the severity of liver fibrosis. This reality presents an urgent clinical challenge, highlighting the need to integrate liver fibrosis assessment into routine cardiovascular risk stratification to effectively manage MASLD as a systemic condition. Within the MASLD spectrum, liver fibrosis stage is a key predictor of both liver-related and all-cause mortality, and its prognostic value also extends to cardiovascular outcomes. Advanced fibrosis acts as an independent risk factor for cardiovascular events, likely reflecting the cumulative burden of metabolic stress, systemic inflamma-tion, and endothelial dysfunction. Consequently, accu-rate fibrosis assessment is a cornerstone of comprehensive risk stratification. To this end, noninvasive tests (NITs) have become standard practice for routine risk assessment, largely replacing liver biopsy. Major international guidelines, including those from the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the European Association for the Study of the Liver (EASL), and the Korean Association for the Study of the Liver (KASL), consistently recommend a widely endorsed 2-step path-way: initial screening with a simple blood-based score, such as the fibrosis-4 (FIB-4) index, followed by an imaging- based test, such as vibration-controlled transient elastog-raphy (VCTE), for those at intermediate or high risk. However, the clinical utility of this pathway is confounded by the presence of type 2 diabetes mellitus (DM). MASLD, type 2 DM, and ASCVD are closely interconnected through shared pathophysiological mechanisms, primarily insulin resistance, which syner-gistically amplify cardiovascular risk. Because type 2 DM is intrinsically a potent risk factor for ASCVD,it raises the critical question of whether the prognostic value of liver fibrosis is attenuated by the high baseline cardiovascular risk conferred by diabetes. Conse-quently, it remains unclear whether fibrosis staging provides a clinically meaningful risk gradient in patients with concomitant MASLD and DM. This knowledge gap has been highlighted by societies such as the American Diabetes Association and the American College of Cardiology/American Heart Association, which have called for more precise risk stratification strategies. Therefore, we aimed to investigate the risk of incident clinical ASCVD among individuals with MASLD, stratified by the guideline-recommended 2- step pathway for identifying advanced fibrosis, and to validate its clinical utility across the entire glycemic spectrum, ranging from normoglycemia to diabetes. ## METHODS ### Study design and population This study was designed as a single-center, retrospec-tive analysis of a health screening cohort. The study ### Page 3 included adult subjects who underwent comprehensive health check-ups at Severance Hospital (Seoul, South Korea) between 2012 and 2020. Subjects who underwent concurrent VCTE and FIB- 4 assessments were initially screened. Subjects who did not meet the diagnostic criteria for MASLD were excluded. To minimize confounding factors and ensure the reliability of NIT evaluations, the following prespe-cified exclusion criteria were applied to the confirmed MASLD cohort: (1) significant alcohol consumption ( > 210 g/wk for men and > 140 g/wk for women); (2) positive serology for hepatitis B or C virus; (3) presence of autoimmune liver disease; (4) a prior history of cardiovascular disease; (5) age under 18 years; and (6) insufficient medical records for fundamental analysis. This study is reported in accordance with the Strength-ening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. This study was conducted in accordance with the principles of the Declaration of Helsinki and the Declaration of Istanbul. The study protocol received approval from the institutional review board of Sever-ance Hospital (IRB No. 4-2025-0032). The requirement for informed consent was waived by the IRB due to the retrospective nature of the study and the use of de- identified data. ### Data collection and definitions Comprehensive clinical and laboratory data were obtained from the electronic medical records. Demo-graphic and clinical variables included age, sex, and body mass index, smoking status, and the presence of underlying comorbidities (DM, hypertension, and dysli-pidemia). Comorbidities were defined based on docu-mented medical history or current medication use. Laboratory variables, measured using standardized laboratory protocols, included platelet count, AST, ALT, GGT, total bilirubin, serum albumin, fasting glucose, hemoglobin A1c (HbA1c), total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and creatinine. MASLD was defined according to the 2023 interna-tional consensus as the presence of evidence of hepatic steatosis on imaging (ultrasound or controlled attenuation parameter of VCTE) plus the presence of at least 1 of 5 cardiometabolic risk factors (overweight/ obesity, hyperglycemia, hypertension, hypertriglyceri-demia, or low HDL-cholesterol). Glycemic status was classified based on HbA1c and fasting glucose levels. DM was defined by a prior diagnosis, use of antidiabetic medication, fasting glucose of ≥ 126 mg/dL, or HbA1c of ≥ 6.5%. Prediabetes was defined as fasting glucose of 100–125 mg/dL or HbA1c of 5.7%–6.4%. Normogly-cemia was defined as not meeting the criteria for diabetes or prediabetes. ### Risk stratification for advanced liver fibrosis Liver fibrosis was assessed using established NITs. The FIB-4 index was calculated using the standard formula of (age [years] × AST [IU/L])/(platelet count [109/L] × ALT [IU/L]1/2). Liver stiffness (LS) and the controlled attenuation parameter were measured using VCTE (FibroScan, EchoSens), which was performed by experienced technicians according to the manufactur-er’s guidelines. VCTE results were considered reliable if they included at least 10 valid measurements and an interquartile range–to-median ratio of < 30%. Data quality was ensured through cross-verification of electronic records, and entries with missing or implausible values for key variables were excluded from the analysis. Following the initial assessments, subjects were stratified to determine their probability of advanced liver fibrosis according to the established clinical pathways, adopting specific risk stratification thresholds from the KASL/EASL and the AGA clinical practice guidelines. According to the KASL/EASL framework, subjects were initially classified based on the FIB-4 index as low risk (FIB-4 < 1.3), intermediate risk (FIB-4 1.3–2.67), or high risk (FIB-4 > 2.67), with an age-adjusted low-risk cutoff of < 2.0 for subjects aged 65 years or older. Subjects at intermediate- or high risk subsequently underwent LS measurement via VCTE. This sequential process resulted in an initial classification into 4 fibrosis severity tiers: low-risk (FIB-4 < 1.3); intermediate-low- risk (FIB-4 ≥ 1.3 and LS < 8.0 kPa); intermediate-high- risk (FIB-4 ≥ 1.3 and LS 8.0–12.0 kPa); and high-risk (FIB-4 ≥ 1.3 and LS ≥ 12.0 kPa). Similarly, under the AGA clinical care pathway, subjects were designated as very low risk if they had an FIB-4 < 1.3 (or < 2.0 for age ≥ 65 y) without comorbid type 2 DM and had minimal metabolic risk factors. All other subjects underwent VCTE evaluation. Based on their LS results, they were further stratified into low-risk (LS ≤ 8.0 kPa), intermediate-risk (LS 8.1–12.0 kPa), and high-risk (LS > 12.0 kPa) groups. ### ASCVD risk assessment The 10-year risk of developing a first hard ASCVD event, defined as nonfatal myocardial infarction, coro-nary heart disease–related death, or fatal/nonfatal stroke, was calculated for each subject using the Pooled Cohort Equations as recommended by the 2019 American College of Cardiology/American Heart Association (ACC/AHA) Primary Prevention Guideline. These equations incorporate age, sex, race, total cholesterol, HDL-cholesterol, systolic blood pressure, antihypertensive medication use, DM status, and current smoking history. In accordance with the ### Page 4 2019 ACC/AHA guidelines, subjects with a calculated 10-year risk score of ≥ 20% were classified as having high baseline ASCVD risk. ### Follow-up and ASCVD event ascertainment The Pooled Cohort Equations were originally designed to predict the 10-year risk of “hard ASCVD” (strictly defined as nonfatal myocardial infarction, fatal coronary heart disease, and fatal or nonfatal stroke). However, given the inherently low incidence of hard ASCVD events anticipated in an asymptomatic health screening cohort, the primary longitudinal endpoint was estab-lished as incident “clinical ASCVD” to ensure adequate statistical power for subsequent multivariable analyses. Consequently, the clinical ASCVD outcome was defined as nonfatal myocardial infarction, fatal coronary heart disease, stable or unstable angina, ischemic stroke, transient ischemic attack, and peripheral artery disease, explicitly excluding nonatherosclerotic condi-tions such as hemorrhagic stroke and nonischemic heart failure. Incident events were ascertained from the institutional electronic medical record database using the relevant International Classification of Dis-eases, Tenth Revision (ICD-10) diagnostic codes (Supplemental Table S3,). For the longitudinal survival analysis, only subjects with available post-baseline clinical records were included. The baseline was established as the date of the initial health check-up. Subjects were followed from baseline until the occurrence of an incident clinical ASCVD event or their last clinical follow-up visit. ### Statistical analysis Baseline characteristics were compared among the glycemic groups using ANOVA or the Kruskal-Wallis test for continuous variables, and the chi-square test for categorical variables. Continuous variables are expressed as mean ± SD or median with interquartile range, while categorical variables are presented as numbers and percentages. To explicitly address poten-tial selection bias inherent to the referral dynamics of health screening cohorts, baseline clinical character-istics were also systematically compared between the subgroup included in the survival analysis and the remaining excluded cohort using the Student t test and chi-square test. Data missingness was handled through complete case analysis, as key variables for fibrosis and ASCVD risk assessment were required for inclusion. For all comparative analyses, the 2 highest risk tiers of each framework—specifically, the intermediate-high and high groups in the KASL/EASL pathway, and the intermediate and high groups in the AGA pathway— were respectively merged into a unified highest-tier classification to ensure robust statistical power. The cumulative incidence of clinical ASCVD events was estimated using Aalen-Johansen estimators, formally treating noncardiovascular death before an ASCVD event as a competing risk. To robustly evaluate the independent associations between baseline fibrosis severity tiers and incident clinical ASCVD, multivariable Fine-Gray subdistribution hazards models were employed. Furthermore, to assess whether the prognostic impact of fibrosis severity on incident ASCVD risk varied by baseline glycemic status, an interaction term (Fibrosis severity tier × Glycemic status) was incorporated into the Fine- Gray model. Consequently, all longitudinal effect estimates are reported as subdistribution hazard ratios (sHRs) with 95% CIs. Two-sided p values < 0.05 were considered statistically significant. All statistical analy-ses were performed using Python (Python Software Foundation) and R software (version 4.1.2; R Founda-tion for Statistical Computing). ## RESULTS ### Baseline characteristics of the study cohort A total of 12,738 subjects who underwent health screening with VCTE and FIB-4 assessments were initially evaluated. Of these, 4766 subjects were excluded as they did not meet the diagnostic criteria for MASLD. Among the 7972 subjects with confirmed MASLD, an additional 1453 were excluded due to competing liver diseases, a prior history of cardiovas-cular disease, or missing data (). Conse-quently, 6519 subjects with MASLD were ultimately included as the baseline cohort and classified accord-ing to their glycemic status: 3243 (49.7%) in the normoglycemia group, 2369 (36.3%) in the prediabetes group, and 907 (13.9%) in the diabetes group. compares the characteristics of the baseline cohort among the 3 groups. Progressing from the normoglycemia group to the prediabetes and diabetes groups, there were statistically significant stepwise increases in age (46.6, 52.9, and 57.1 y, respectively), body mass index (24.2, 25.8, and 26.0 kg/m2, respec-tively), prevalence of hypertension (11.5%, 23.0%, and 41.6%, respectively), and prevalence of dyslipidemia (12.2%, 20.9%, and 37.9%, respectively) (all p < 0.001). The cardiovascular risk profile also showed a clear association with worsening glycemic status. The mean 10-year ASCVD risk score showed a substantial increase from 3.4% in the normoglycemia group to 6.2% in the prediabetes group and 15.2% in the ### Page 5 diabetes group (p < 0.001). The proportion of subjects with high ASCVD risk ( ≥ 20%) also increased expo-nentially: 1.4% in the normoglycemia group, 4.1% in the prediabetes group, and 25.6% in the diabetes group (p < 0.001). The FIB-4 index also increased significantly from the normoglycemia group (1.07) to the pre-diabetes (1.22) and diabetes (1.42) groups (p < 0.001). To address potential selection bias inherent in the referral dynamics of health screening cohorts, we systematically compared the baseline characteristics ![FIGURE1]() ### Page 6 of subjects included in the survival analysis cohort (n = 3221) with those excluded due to absent follow-up records (n = 3298) (Supplemental Table S1,). The survival analysis cohort was slightly older (mean age 52.3 vs. 48.4 y, p < 0.001) and had a higher prevalence of metabolic comorbid-ities, including diabetes (15.9% vs. 11.9%, p < 0.001) and hypertension (22.3% vs. 17.6%, p < 0.001). This pattern aligns with typical clinical dynamics, where individuals with underlying comorbidities are more likely to undergo regular hospital follow-ups. Crucially, baseline LS measurements did not significantly differ between the included and excluded cohorts (mean 4.2 vs. 4.2 kPa, p = 0.188), indicating that the baseline severity of hepatic fibrosis was not fundamentally skewed by follow-up attrition. ### Page 7 ### Distribution of liver fibrosis severity by glycemic status The distribution of fibrosis severity tiers according to the KASL/EASL pathway showed a significant difference across glycemic states (p < 0.001) (). In the normoglycemia group, 77.8% (n = 2522) of the baseline cohort were classified as low tier. This proportion decreased to 70.7% (n = 1675) in the prediabetes group and further to 61.9% (n = 561) in the diabetes group. Conversely, the proportion of subjects in the interme-diate-high/high tier progressively increased with wor-sening glycemic status: 1.3% (n = 42) in the normogly-cemia group, 2.3% (n = 54) in the prediabetes group, and 5.8% (n = 53) in the diabetes group (p < 0.001). When applying the AGA pathway (Supplemental Table S2,), the distribution of fibrosis risk tiers among patients with diabetes demon-strated a distinct pattern. Specifically, no diabetic patients were classified into the very low tier (0%), while the vast majority (97.8%, n = 887) were catego-rized into the low tier.### Baseline ASCVD risk prediction according to fibrosis severity and glycemic status Baseline predicted 10-year ASCVD risk scores were evaluated according to fibrosis severity tiers and glycemic status. A sequential increase in the median 10-year ASCVD risk was observed across fibrosis severity tiers within all glycemic groups (). In ### Page 8 ### Page 9 the normoglycemia group, the median risk was 1.3% in the low tier and 8.5% (n = 42) in the intermediate-high/ high tier (p < 0.001). This pattern was also observed in the prediabetes group, where the median risk increased from 3.6% in the low tier to 12.0% (n = 54) in the intermediate-high/high tier (p < 0.001). In the diabetes group, the median 10-year ASCVD risk was 10.5% in the low tier and 16.4% (n = 53) in the intermediate-high/ high tier (p < 0.001). A corresponding pattern was observed regarding the proportion of subjects categorized as having high predicted ASCVD risk ( ≥ 20%). In the normoglycemia group, this proportion increased from 1.0% in the low tier to 11.9% in the intermediate-high/high tier (p < 0.001). In the prediabetes group, the proportion of high-risk subjects increased from 3.2% in the low tier to 35.2% in the intermediate-high/high tier (p < 0.001). In the diabetes group, the proportion of high-risk subjects was 25.8% in the low tier and 41.5% in the intermedi-ate-high/high tier (p < 0.001). ### Impact of glycemic status on the prognostic performance of fibrosis severity stratification For the longitudinal survival analysis, incident clinical ASCVD events and 5-year cumulative incidence ![FIGURE2]() ### Page 10 probabilities were assessed across the KASL/EASL and AGA fibrosis severity tiers, stratified by baseline glycemic status. A total of 269 incident clinical ASCVD events were observed among the 3221 subjects in the survival analysis cohort. Based on the KASL/EASL pathway ( and), both 5-year cumulative incidence and adjusted sHR demonstrated that the prognostic impact of advanced fibrosis varied significantly according to glycemic status. Among subjects with normoglycemia, the 5-year cumulative incidence was 7.8% in the low tier, and increased to 17.7% in the intermediate-high/ high tier; however, this did not translate to a statistically significant increase in relative hazard after multivariable adjustment (intermediate-high/high: sHR: 2.33, 95% CI: 0.73–7.42). In contrast, in the prediabetes group, a significant stepwise increase was observed for both absolute and relative risks. The 5-year cumulative incidence sequentially increased from 9.5% in the low tier to 22.0% in the intermediate-high/high tier, which corresponded to a significantly exacerbated relative risk (sHR: 2.62, 95% CI: 1.14–6.01, p = 0.024). Conversely, in the diabetes group, this risk gradient was no longer evident. The 5-year cumulative incidence was uniformly high across all fibrosis tiers (18.5%, 15.8%, and 15.2%, respectively). Furthermore, multivariable analysis revealed that the relative hazard did not significantly increase in either the intermediate-low (sHR: 0.92, 95% CI: 0.56–1.52, p = 0.750) or the intermediate-high/high tiers (sHR: 0.91, 95% CI: 0.33–2.48, p = 0.850) com-pared with the low tier. Parallel analyses were performed using the AGA pathway (Supplemental Table S4, and). However, because the AGA “very low” risk tier requires the absence of diabetes by definition, no subjects were assigned to this tier within the diabetes group, preventing its use as a universal reference. In addition, no incident ASCVD events were observed in the highest risk tiers among the normoglycemia and diabetes groups. Conse-quently, sHRs could not be reliably estimated for these specific strata. ### Subgroup analyses by age and glycemic control When comparing baseline characteristics within the survival analysis cohort (n = 3221) by age (Supplemen-tal Table S5,), the elderly group ( ≥ 65 y) demonstrated a markedly higher baseline 10-year ASCVD risk score compared with the younger group ( < 65 y) (20.17% vs. 4.94%, p < 0.001), despite identical baseline LS (4.14 vs. 4.15 kPa,p = 0.885). When stratifying the survival analysis by these age groups (Supplemental Table S6,), the intermediate and high-risk tiers of the KASL/EASL pathway did not reach statistical significance in either age group after multi-variable adjustment, although a nonsignificant trend toward increased risk was observed in the younger cohort. Similarly, for the AGA pathway, sHR could not be calculated for the highest risk tiers due to the absence of incident ASCVD events across both age groups. Furthermore, to address the impact of glycemic control within the diabetes group, baseline character-istics of the diabetic survival analysis cohort (n = 513) were compared (Supplemental Table S7,). The suboptimal control group (HbA1c ≥ 6.5%) exhibited a significantly higher baseline 10-year ASCVD risk score compared with the optimal control group (HbA1c < 6.5%) (16.50% vs. 13.01%,p = 0.002), whereas baseline LS was identical (4.26 vs. 4.27 kPa, p = 0.939). In the subsequent survival analysis (Supplemental Table S8,), neither the optimal nor the suboptimal glycemic control subgroup demonstrated a significantly increased relative hazard for incident ASCVD across the interme-diate or high-risk fibrosis tiers compared with the low tier (all p > 0.05). Similarly, when applying the AGA pathway to these subgroups, sHRs could not be estimated because no subjects with diabetes were assigned to the very low-risk tier, and no incident ASCVD events occurred in the intermediate/high-risk tier. ## DISCUSSION The recent transition in nomenclature from NAFLD to MASLD reflects the close relationship between hepatic steatosis and systemic metabolic dysfunction, including ASCVD risk. However, data on whether noninvasive liver fibrosis assessment provide additional clinical information for ASCVD risk assessment across differ-ent glycemic states remain limited. In this study, we evaluated whether fibrosis severity assessed using sequential noninvasive pathways was associated with incident ASCVD across different glycemic states in patients with MASLD. Our findings suggest that the relationship between fibrosis severity and incident ASCVD differs according to baseline glycemic status. The observed relationship between fibrosis severity and ASCVD outcomes is consistent with the known pathophysiology of MASLD. The liver is not only a target organ of metabolic injury but also contributes to systemic inflammation and atherogenesis. Liver fibrosis reflects the cumulative burden of such meta-bolic injury over time. Advanced fibrosis has been associated with systemic oxidative stress, endothelial dysfunction, increased carotid intima-media thickness, and coronary artery calcification. In the outcome- based analysis, the association between fibrosis severity and incident ASCVD was mainly observed in ### Page 11 ### Page 12 patients with prediabetes (). In this subgroup, the 5-year cumulative incidence increased across fibrosis severity tiers, and the highest fibrosis tier showed a higher adjusted sHR for incident ASCVD. In patients with normoglycemia, the cumulative incidence and adjusted sHR tended to increase with higher fibrosis severity, although these associations did not reach statistical significance. In a supplementary analysis combining normoglycemia and prediabetes as a non-diabetes group, higher fibrosis severity in the KASL/EASL pathway remained associated with increased incident ASCVD, whereas this pattern was not observed in patients with diabetes (Supplemental Table S10,). These findings were consistent with the primary analysis, while the separate evaluation of normoglycemia, prediabetes, and diabetes further showed that the association was mainly driven by the prediabetes subgroup. The association between fibrosis severity and incident ASCVD also differed by age. In the elderly cohort ( ≥ 65 y), the relative hazard for incident ASCVD did not increase significantly across fibrosis severity tiers (Supplemental Table S6,). This may be because age itself is a major determinant of ASCVD risk, limiting the additional stratification provided by fibrosis severity in older patients. In contrast, among younger individuals, higher fibrosis severity was associated with greater incident ASCVD risk. These findings suggest that fibrosis assessment may be useful in identifying younger patients with MASLD who have higher ASCVD risk despite their lower age-based risk. In patients with diabetes, the AGA pathway classified most individuals into the low fibrosis tier, which limited assessment of ASCVD risk across fibrosis severity tiers (Supplemental Table S4,). The KASL/EASL pathway provided a broader ![FIGURE3]() ### Page 13 distribution; however, higher fibrosis severity was not associated with a higher 5-year cumulative incidence or adjusted sHR for incident ASCVD in this subgroup (). A supplementary analysis stratified by glycemic control among patients with diabetes showed similar findings (Supplemental Table S8,). Higher fibrosis tiers were not consistently associated with increased incident ASCVD in either the optimal or suboptimal glycemic control groups, although interpretation was limited by the small number of patients and events in the highest fibrosis tiers. Overall, these findings support a tailored approach to ASCVD risk assessment in MASLD. Our data do not support using FIB-4/VCTE-based pathways as inde-pendent ASCVD prediction tools or as replacements for established ASCVD risk calculators. Rather, fibrosis severity assessed during MASLD evaluation may provide additional clinical information, particularly in patients with prediabetes or younger individuals. For hepatologists, the detection of higher fibrosis severity may support closer review of cardiometabolic risk factors and consideration of cardiovascular evaluation in these selected subgroups. Our study has several limitations. First, the retro-spective, cross-sectional nature of the primary cohort limits causal inference. To address this issue, we integrated a longitudinal survival analysis cohort and evaluated incident ASCVD events during follow-up. Second, as a single-center study, we cannot exclude the possibility that some ASCVD events were missed if patients presented to other hospitals. To reduce this bias, patients were censored at the date of their last clinical encounter. Future validation using nationwide claims databases would help address this limitation. Third, liver fibrosis severity was determined by NITs rather than histological confirmation via liver biopsy; however, VCTE is widely used and validated for noninvasive fibrosis assessment in MASLD and is more feasible than biopsy in large-scale clinical cohorts. Fourth, selection bias may exist because the cohort was derived from health screening partici-pants. We compared the survival analysis cohort with excluded subjects and found no significant difference in baseline LS (Supplemental Table S1,). Fifth, we did not perform time-depen-dent AUC analyses or direct comparisons with estab-lished ASCVD prediction models. Therefore, our findings should not be interpreted as validating FIB-4/ VCTE-based pathways as standalone ASCVD predic-tion tools. Rather, they suggest that fibrosis assess-ment may provide additional clinical information when interpreted together with established cardiometabolic risk factors. Finally, the single-ethnicity Asian cohort may also limit generalizability, and external validation in other populations is needed. In conclusion, higher liver fibrosis severity assessed by NITs was associated with incident ASCVD outcomes in selected MASLD subgroups, particularly patients with prediabetes and younger individuals. Fibrosis assessment may help identify patients who warrant closer cardiometabolic evaluation when interpreted alongside established ASCVD risk prediction tools. ## FUNDING INFORMATION This work was supported by a faculty research grant of Yonsei University College of Medicine (6-2020-0130). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ## CONFLICTS OF INTEREST The authors have no conflicts to report. ## ORCID Jaehong Jeong Jung Pyo Hong Dong Yun Kim Jae Seung Lee Mi Na Kim Jeong Eun Song Hyun Chin Cho Beom Kyung Kim Jun Yong Park Do Young Kim Sang Hoon Ahn Hye Won Lee Seung Up Kim ## REFERENCES - 1. Michalopoulou E, Thymis J, Lampsas S, Pavlidis G, Katogiannis K, Vlachomitros D, et al. The triad of risk: linking MASLD, cardiovascular disease and type 2 diabetes; from pathophysio-logy to treatment. J Clin Med. 2025;14:428. - 2. Cusi K, Abdelmalek MF, Apovian CM, Balapattabi K, Bannuru RR, Barb D, et al. 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