Abstract
BACKGROUND AND OBJECTIVE: This study aimed to elucidate the role of insulin resistance in the progression from non-alcoholic fatty liver disease (NAFLD) to cardiovascular-kidney-metabolic (CKM) diseases, and to explore the potential influence of lifestyle factors. METHODS: This study included participants free of NAFLD and CKM diseases from the UK Biobank. Insulin resistance was assessed using the TyG index. CKM diseases include ischemic stroke (IS), ischemic heart disease (IHD), type 2 diabetes (T2D), and chronic kidney disease (CKD). Markov multi-state models were used to assess the associations between the TyG index and disease transitions. RESULTS: Among 377,757 participants (median age 57 years), 4949 developed NAFLD over a median follow-up of 13.6 years. Of these, 12.65% progressed to T2D, 9.11% to IHD, 8.63% to CKD, and 4.61% to IS. Elevated TyG levels significantly accelerated transitions from NAFLD to first-onset CKM disease (HR = 1.25, 95% CI 1.05-1.49), double CKM disease (HR = 1.46, 95% CI 1.19-1.80), and triple CKM disease (HR = 1.81, 95% CI 1.28-2.55). Similar progression risk increases were observed for individual CKM components: T2D (HR = 1.41, 95% CI 1.11-1.78), CKD (HR = 1.37, 95% CI 1.08-1.75), and IS (HR = 1.70, 95% CI 1.27-2.27). A J-shaped dose-response relationship was identified. Transitions risk remained pronounced among individuals with healthy sleep and regular physical activity. CONCLUSIONS: Insulin resistance independently accelerated the progression from NAFLD to CKM diseases, particularly ischemic stroke. Healthy sleep and regular physical activity failed to offset this detrimental impact.