Growth differentiation factor-15 and the incidence, bidirectional progression, and risk prediction of atherosclerotic cardiovascular disease and metabolic dysfunction-associated steatotic liver disease in individuals with cardiovascular-kidney-metabolic syndrome stages 0–3

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a circulating biomarker reflecting oxidative stress, inflammation, and cellular aging. However, its role in disease risk assessment amongst individuals with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 remains unclear. METHODS: This study included 29,697 UK Biobank participants with CKM stages 0-3 defined in accordance with the American Heart Association criteria. Associations of GDF-15 with metabolic, inflammatory and liver fibrosis markers and CKM stage were examined using linear or multinomial logistic regression models. Fine-Gray competing risk regression models were used to evaluate associations with incident atherosclerotic cardiovascular disease (ASCVD), metabolic dysfunction-associated steatotic liver disease (MASLD) and their comorbidity (coexistence of both conditions). Bidirectional disease transitions were assessed using a multi-state Markov model. The relative importance of GDF-15 was evaluated using SHapley Additive exPlanations (SHAP) and likelihood ratio (LR) statistics. Improvements in risk prediction models were assessed using time-dependent area under the receiver operating characteristic curve, Brier score, integrated discrimination improvement and continuous net reclassification improvement. RESULTS: ) after multivariable adjustment for age, sex, smoking status, body mass index, diabetes mellitus, glycated haemoglobin, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, creatinine, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, cystatin C, Townsend deprivation index, physical activity, and CKM stage. These associations remained consistent across subgroup analyses. Multi-state analyses indicated that GDF-15 predicted bidirectional progression between ASCVD and MASLD, with 10-year cumulative incidences of ASCVD and MASLD reaching 15.75% and 2.03%, respectively, among individuals in the top 10% of GDF-15 levels, and further increasing to 20.05% and 2.32% in those in the top 5%. SHAP and LR analyses showed that GDF-15 had high relative importance in predicting ASCVD and MASLD. Incorporating GDF-15 into established risk scores (PREVENT, SCORE2, FLI, FIB-4 and ARPI) showed modest improvements in risk discrimination, reclassification, and prediction error, particularly for ASCVD. In several settings, GDF-15 outperformed established biomarkers, including insulin resistance, systemic inflammation, apolipoprotein A/B, lipoprotein(a), cardiac troponin I, and N-terminal prohormone of brain natriuretic peptide. CONCLUSIONS: GDF-15 may serve as a promising biomarker for cardiovascular-kidney-liver-metabolic syndrome risk stratification and management.