Serial fibrosis-4 variability and longitudinal patterns are associated with incident heart failure in type 2 diabetes: a 24-month landmark cohort study
5 affiliations
- 1Department of Epidemiology, Faculty of Health Sciences, University of Debrecen
- 2Department of Integrative Health Sciences, Institute of Health Sciences, Faculty of Health Sciences, University of Debrecen
- 3Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen
- 4Institute of Health Studies, Faculty of Health Sciences, University of Debrecen
- 5Eötvös Loránd Research Network–University of Debrecen (ELKH-UD) Vascular Pathophysiology Research Group 11003, University of Debrecen
Abstract
Background: The prognostic relevance of serial Fibrosis-4 index (FIB-4) changes for incident heart failure (HF) in type 2 diabetes mellitus (T2DM) remains unclear. We examined whether within-person FIB-4 variability and longitudinal patterns were associated with HF after explicit adjustment for chronological age.
Methods: Routinely collected clinical data from 2000 to 2025 were analyzed using a 24-month landmark design. FIB-4 measurements from months 0 to 18 defined the exposure, followed by a 6-month lag before HF follow-up. Variability was calculated as the within-person standard deviation of log ₂ -transformed FIB-4. Using a threshold of 2.67, patients were classified as never high, improving from high, worsening to high, or persistently high. Associations with incident HF were estimated using multivariable Cox regression.
Results: Among 8,221 patients, 1,811 developed HF during 50,640 person-years. Greater FIB-4 variability was associated with a higher HF hazard (adjusted hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.43–2.09). Compared with the never-high pattern, persistent-high FIB-4 (HR, 1.73; 95% CI, 1.35–2.20) and worsening to high (HR, 1.28; 95% CI, 1.01–1.62) were associated with higher HF hazards, whereas improving from high was not (HR, 0.95; 95% CI, 0.70–1.28). Adding serial FIB-4 features resulted in a small, statistically uncertain improvement in temporal-validation discrimination (ΔC-index, 0.0069; 95% CI, −0.0043 to 0.0190).
Discussion: Serial FIB-4 variability and persistent elevation were associated with incident HF independently of chronological age. These measures may characterize longitudinal multisystem cardiometabolic burden, but their incremental predictive value was limited. External validation is required before clinical application.
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BibTeX
@article{nagy2026serial,
title = {{Serial fibrosis-4 variability and longitudinal patterns are associated with incident heart failure in type 2 diabetes: a 24-month landmark cohort study}},
author = {Attila Csaba Nagy and Amr Sayed Ghanem and Battamir Ulambayar and Marianna Móré and Mariann Harangi},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1963810},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1963810/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Serial fibrosis-4 variability and longitudinal patterns are associated with incident heart failure in type 2 diabetes: a 24-month landmark cohort study
AU - Attila Csaba Nagy
AU - Amr Sayed Ghanem
AU - Battamir Ulambayar
AU - Marianna Móré
AU - Mariann Harangi
PY - 2026
DA - 2026/10/15
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1963810
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1963810/full
AB - Background: The prognostic relevance of serial Fibrosis-4 index (FIB-4) changes for incident heart failure (HF) in type 2 diabetes mellitus (T2DM) remains unclear. We examined whether within-person FIB-4 variability and longitudinal patterns were associated with HF after explicit adjustment for chronological age. Methods: Routinely collected clinical data from 2000 to 2025 were analyzed using a 24-month landmark design. FIB-4 measurements from months 0 to 18 defined the exposure, followed by a 6-month lag before HF follow-up. Variability was calculated as the within-person standard deviation of log ₂ -transformed FIB-4. Using a threshold of 2.67, patients were classified as never high, improving from high, worsening to high, or persistently high. Associations with incident HF were estimated using multivariable Cox regression. Results: Among 8,221 patients, 1,811 developed HF during 50,640 person-years. Greater FIB-4 variability was associated with a higher HF hazard (adjusted hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.43–2.09). Compared with the never-high pattern, persistent-high FIB-4 (HR, 1.73; 95% CI, 1.35–2.20) and worsening to high (HR, 1.28; 95% CI, 1.01–1.62) were associated with higher HF hazards, whereas improving from high was not (HR, 0.95; 95% CI, 0.70–1.28). Adding serial FIB-4 features resulted in a small, statistically uncertain improvement in temporal-validation discrimination (ΔC-index, 0.0069; 95% CI, −0.0043 to 0.0190). Discussion: Serial FIB-4 variability and persistent elevation were associated with incident HF independently of chronological age. These measures may characterize longitudinal multisystem cardiometabolic burden, but their incremental predictive value was limited. External validation is required before clinical application.
SN - 1664-2392
ER -