Hepatic metabolic burden and all-cause mortality across glucose metabolism statuses in a cardiovascular-kidney-metabolic syndrome population: insights from the National Health and Nutrition Examination Survey (NHANES)

BACKGROUND: Hepatic metabolic burden is an integral component of cardiometabolic risk. However, the association of hepatic metabolic burden assessed by the fatty liver index (FLI) with all-cause mortality in cardiovascular-kidney-metabolic (CKM) syndrome has not been well described when individuals are stratified by glucose metabolism status. Therefore, this study aimed to evaluate the association between FLI and all-cause mortality across different glucose metabolism states in adults with CKM syndrome. METHODS: Data were derived from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Adults with CKM syndrome according to the AHA/ADA framework were included and categorized by glucose metabolism status as normoglycemia, prediabetes, or diabetes. Hepatic metabolic burden was assessed using FLI. Weighted multivariable Cox proportional hazards models and restricted cubic spline (RCS) analyses were applied to examine the associations between FLI and all-cause mortality across glucose metabolism status. Additionally, joint analyses with combined FLI (FLI ≥ 60 vs. <60) and glycemic categories and multiple sensitivity analyses were performed. RESULTS: Among 19,107 participants with CKM syndrome (weighted N = 105,007,226), 2482 deaths occurred over a median follow-up of 9.42 years. No robust independent association was observed between FLI and all-cause mortality among individuals with normoglycemia or prediabetes after multivariable adjustment. In contrast, among individuals with diabetes, multivariable Cox regression and RCS analysis indicated that higher FLI was significantly associated with increased mortality risk and demonstrated a J-shaped nonlinear dose-response relationship. Joint analyses further showed that elevated FLI was associated with progressively higher death risk in the presence of impaired glucose metabolism, with the highest risk observed among individuals with diabetes and FLI ≥ 60. Multiple sensitivity analyses confirmed that the main analysis results were robust. CONCLUSIONS: Within the CKM syndrome spectrum, elevated FLI was associated with a higher risk of all-cause mortality among individuals with diabetes, with a J-shaped association, whereas the association between FLI and all-cause mortality was not significant among individuals with normoglycemia or prediabetes. These findings suggest that the relationship between FLI and mortality in CKM populations may vary according to glycemic status and highlight the importance of considering glycemic context when interpreting liver-related metabolic markers.