Aims: As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations.

Methods and results: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)- Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9mg/dL) compared to central (median 7.9mg/ dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere-Terpstra test P< 0.001). Kaplan-Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels≥90th percentile (log-rank test: P< 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE [95% confidence interval (CI) 1.15- 1.46] and of 1.25 for CVD (95% CI 1.12-1.39) for Lp(a) levels in the 67-89th percentile and a HR of 1.49 for MCE (95% CI 1.29-1.73) and of 1.44 for CVD (95% CI 1.25-1.65) for Lp(a) levels≥ 90th percentile vs. Lp(a) levels in the lowest third (P< 0.001 for all). There was no significant association between Lp(a) levels and total mortality Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes [HR for MCE 1.31 (95% CI 1.15-1.50)] and for CVD 1.22 (95% CI 1.08-1.38) compared to those without diabetes [HR for MCE 1.15 (95% CI 1.08-1.21; HR for CVD 1.13 (1.07-1.19)] while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD).

Conclusion: In this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies.