Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study

Background The Fibrosis-4 Index (FIB-4) is used as a non-invasive tool for the presence of advanced liver fibrosis in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, evidence for an association between FIB-4 and risk of mortality and/or liver-related clinical outcomes is limited. The aim of this study was to investigate the association between FIB-4 and subsequent liver events, cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes examined in routine general practice. Methods This was a longitudinal cohort study in which eligible adults had obesity and/or type 2 diabetes and >= 1 FIB-4 score calculable from UK Clinical Practice Research Datalink GOLD after 1 January 2001. No alcohol-related disorders and/or chronic liver diseases (except non-alcoholic fatty liver disease) and/or no prescriptions of drugs inducing liver disease were permitted. Individuals were followed until time of first event, 10 years, or 1 January 2020. Analyses were conducted using Aalen-Johansen cumulative incidence functions and Cox proportional hazards models. Findings Among 44,481 included individuals (mean age 588 years; 54% female), there were 979 liver, 6002 cardiovascular, and 8971 mortality events during the 10 years of follow-up. At 10 years, the cumulative incidence of liver events in the high (>267), indeterminate (130-267), and low (<130) baseline FIB-4 risk groups were 15%, 3%, and 1%, respectively. Age- and sex-adjusted hazard ratios (HRs) for liver events were elevated in high (1646; 95% confidence interval [CI] 1365-1985) and indeterminate (245; 95% CI 207-290) versus low FIB-4 risk groups. Similar results were found for cardiovascular events and all-cause mortality. Among 20,433 individuals with >= 2 FIB-4 measurements, increase/decrease in FIB-4 12 months after baseline was directly associated with risk of liver events: compared with individuals with low baseline FIB-4 and no change in FIB-4 (reference), the adjusted HR (95% CI) for those with high baseline FIB-4 was 2427 (1698-3468) with a one-unit FIB-4 increase, and 1090 (790-1505) with a one-unit decrease. Interpretation In addition to its value as a diagnostic tool, FIB-4 has clinical utility as a prognostic biomarker. Sequential measurement provides a pragmatic, tractable monitoring biomarker that refines risk assessment for liver events, cardiovascular events, and mortality.