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

Abstract

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. 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. 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. 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 a priori ty subgroup for earlier identification and transition-specific risk assessment.