AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Aggressive versus Moderate Lipid-Lowering Therapy Across the Lipoprotein(a) Spectrum: A Cardiovascular Outcomes Study Using Real-World Data
By Hedman H, Sagers L, Dermon J et al.
Background: Lipoprotein(a) (Lp(a)) is a well-established cardiovascular risk factor. Contemporary lipid management extends beyond statins to PCSK9 inhibitors and ezetimibe, enabling more aggressive LDL lowering than was previously achievable; whether such intensification reduces major adverse cardiovascular events (MACE) among Lp(a)-tested patients, and whether benefit differs by Lp(a) level, remains poorly characterized in real-world data. This study aims to assess the association between aggressive versus moderate LDL-lowering therapy and MACE among lipid-treated patients, and whether the association is modified by Lp(a) level. Methods: Lipid-treated adults with ≥1 Lp(a) measurement and ≥6 months of follow-up were identified from the Dandelion Health real-world clinical data platform, from 2016-2025. Using an active-comparator design, exposure was defined as aggressive LDL-lowering therapy (high-intensity statin, PCSK9 inhibitor, or ezetimibe) versus moderate-intensity statin therapy alone; Lp(a) was stratified by elevated - defined as ≥50 mg/dL or ≥125 nmol/L - vs. not. The primary outcome was three-point MACE (all-cause mortality, non-fatal myocardial infarction, and non-fatal ischemic stroke). Associations were assessed using adjusted Cox proportional hazards models in a 1:1 propensity-score (PS) matched cohort with pair-clustered variance. PS matched cohorts were generated from a logistic model that included major cardiovascular risk factors, including demographics, comorbid conditions, and concomitant medication use; a treatment-by-Lp(a) interaction tested effect modification. Results: Among 21,562 eligible adults, 5,291 were lipid-treated, of whom approximately half initiated aggressive and half moderate therapy. PS matching yielded 2,063 balanced pairs (all standardized mean differences <0.1). Aggressive LDL-lowering therapy was associated with a lower rate of MACE (adjusted hazard ratio 0.49, 95% CI 0.25-0.98). The association was directionally consistent among Lp(a)-elevated and non-elevated patients, with no significant effect modification by Lp(a) (interaction p=0.66). Conclusion: In this contemporary, real-world data active-comparator analysis, aggressive LDL-lowering therapy was associated with a lower risk of MACE among lipid-treated patients, irrespective of Lp(a) status. These findings highlight the importance of considering LDL-lowering intensity in Lp(a) clinical trial design. If aggressive LDL-lowering reduces MACE similarly across Lp(a) strata, then differences in LDL management could attenuate or obscure the incremental benefit of Lp(a)-lowering therapies. Ensuring balanced and optimized LDL-C treatment across study arms may be critical for isolating the true effect of Lp(a) reduction on cardiovascular outcomes. Future studies will validate these findings and incorporate multimodal data sources.