Elevated Lp(a) and insulin resistance jointly double cardiovascular mortality risk in MASLD, UK Biobank analysis of 101,348 (Cardiovasc Diabetol 2026)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk. Lipoprotein(a) [Lp(a)] and insulin resistance (IR) are established cardiovascular risk factors, yet their joint associations with cardiovascular outcomes in MASLD remain poorly understood.

Methods: We analyzed data from the UK Biobank and included 101,348 adults with MASLD for CVD mortality analyses and 94,089 individuals without baseline CVD for incident CVD analyses. IR was assessed using the triglyceride-glucose (TyG) index. Participants were categorized according to Lp(a) levels (< 125 vs. ≥ 125 nmol/L) and TyG index (low vs. high, defined by the 75th percentile) and further classified into four joint Lp(a)/IR groups, with low Lp(a)/low IR serving as the reference group. Cox proportional hazards models were used to evaluate associations of Lp(a), TyG, and their combined categories with incident CVD and CVD mortality.

Results: During a median follow-up of 15.7 years, elevated Lp(a) and higher TyG levels were each independently associated with increased risks of incident CVD and CVD mortality, regardless of each other's status. In the fully adjusted model, each SD increase in Lp(a) was associated with a 14% higher risk of CVD mortality (HR, 1.14; 95% CI 1.10-1.19; P < 0.001) and a 9% higher risk of incident CVD (HR, 1.09; 95% CI, 1.07-1.11; P < 0.001). Similarly, each SD increase in TyG was associated with a 27% higher risk of CVD mortality (HR, 1.27; 95% CI 1.21-1.34; P < 0.001) and a 9% higher risk of incident CVD (HR, 1.09; 95% CI 1.07-1.12; P < 0.001). Compared with participants in the reference group with Lp(a) < 125 nmol/L and low IR, those with concomitantly elevated Lp(a) and high IR exhibited the highest cardiovascular risk, with adjusted HRs of 2.04 (95% CI 1.63-2.55) for CVD mortality and 1.49 (95% CI 1.35-1.64) for incident CVD (both P < 0.001), with a significant dose-response trend across groups (P for trend < 0.001). These associations remained consistent across subgroups stratified by age, sex, obesity, diabetes, and hypertension.

Conclusions: Elevated Lp(a) and IR were independently associated with adverse cardiovascular outcomes in MASLD, with the highest risk observed among individuals with concomitant elevations in both markers.