Associations of cardiometabolic burden with cardiovascular disease-death transitions in metabolic dysfunction-associated steatotic liver disease: a prospective cohort study using multistate analysis.

Aim: To examine the associations of cardiometabolic burden with transitions from CVD-free status to incident CVD, death without prior CVD, and death after CVD among individuals with MASLD, and to further characterize non-linear patterns, temporal variations, and potential contributing factors related to these associations. Methods: This prospective cohort analysis included 72,922 UK adults with MASLD. Cardiometabolic burden was primarily assessed by the number of cardiometabolic risk factors, with an internally derived weighted score evaluated as a complementary secondary measure. Traditional Cox models estimated overall associations with incident CVD and death, whereas multistate models quantified transition-specific associations. Penalised splines assessed non-linearity, piecewise Cox models evaluated time-stratified associations, and mediation analyses examined inflammatory and lifestyle-related factors. Results: Over a median follow-up of 15.9 years, 15,352 participants developed CVD, 4,273 died without prior CVD, and 4,228 died after incident CVD. Each additional cardiometabolic risk factor was associated with higher risks of the baseline-to-CVD, baseline-to-death, and CVD-to-death transitions (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.15-1.19; HR 1.09, 95% CI 1.06-1.13; and HR 1.13, 95% CI 1.10-1.17, respectively). Corresponding estimates per 1-standard deviation increase in the weighted score were HR 1.23 (95% CI 1.20-1.25), HR 1.12 (95% CI 1.08-1.16), and HR 1.19 (95% CI 1.15-1.23), respectively. Associations with incident CVD were stronger during early follow-up, whereas death-related associations became more apparent over longer follow-up. Significant age interactions were observed, with stronger associations among participants aged <60 years (P for interaction <0.05). In mediation analyses, estimated indirect proportions were generally <3% for circulating inflammatory markers and were larger for smoking and drinking status. Conclusion: Among individuals with MASLD, greater cardiometabolic burden was associated with all disease-state transitions, most strongly with incident CVD. Death-related associations became more apparent over longer follow-up, supporting sustained cardiometabolic surveillance. Associations were more pronounced in younger participants, suggesting that individuals under 60 years with high cardiometabolic burden may be