Association of Plasma Lipoprotein(a) With Major Adverse Cardiovascular Events in MASLD With or Without Advanced Liver Fibrosis

BACKGROUND AND AIMS: There is uncertainty regarding the role of plasma lipoprotein(a) [Lp(a)] in predicting cardiovascular events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We examined the association between plasma Lp(a) concentrations and major adverse cardiovascular events (MACE) in MASLD, stratified by the severity of liver fibrosis. METHODS: This study enrolled patients with MASLD from two centres. Lp(a) percentile groups were generated with the reference group set at the 1st-50th Lp(a) percentiles. High Lp(a) levels correspond to the 91st-100th percentile. Advanced liver fibrosis was defined using the fibrosis (FIB)-4 index > 2.67. MACE was defined as myocardial infarction, ischemic stroke, or cardiovascular death. Cox regression was used to assess the association between the Lp(a) percentile groups and MACE. RESULTS: A total of 56 168 patients with MASLD were followed for a median of 5.0 years (IQR: 2.0-8.5 years), and 6136 patients developed incident MACE. There was an inverse association between Lp(a) percentiles and advanced liver fibrosis (91st-100th percentile, adjusted OR = 0.65, 95% CI 0.59-0.72; p < 0.001). In patients with advanced liver fibrosis, there was a lower proportion in the high Lp(a) levels group (p < 0.001), although the incidence of MACE remained high. MASLD patients with advanced liver fibrosis and high Lp(a) levels had a higher risk of MACE (adjusted HR = 1.56, 95% CI 1.27-1.91; p < 0.001) than those with low Lp(a) levels. CONCLUSIONS: Plasma Lp(a) levels are lower in MASLD patients with advanced fibrosis, yet their MACE risk remains high, suggesting that relying on Lp(a) alone may underestimate cardiovascular risk if advanced liver fibrosis is not considered.