AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Lipoprotein(a) and Residual Vascular Risk Among Patients Achieving Optimal LDL-C: A Real-World Cohort Analysis
By Mojarrad Sani M, Nouri A, Abdollahi A et al.
Background: Elevated lipoprotein(a) [Lp(a)] is a heritable, independent risk factor for atherosclerotic cardiovascular disease, and it is not meaningfully reduced by statins or ezetimibe. Whether elevated Lp(a) translates into measurable residual cardiovascular and limb ischemic risk in patients who have achieved an LDL-C goal of <70 mg/dL on these therapies has not been well established, and the magnitude of this risk in primary versus secondary prevention populations remains uncertain. Research Question: Is elevated Lp(a) associated with higher residual cardiovascular and limb ischemic risk in patients with LDL-C <70 mg/dL on statin and/or ezetimibe therapy? Methods: We used the TriNetX Research Network to identify adults (≥18 years) with at least one LDL-C <70 mg/dL on statin and/or ezetimibe therapy and a documented Lp(a) measurement. Patients on PCSK9 inhibitors were excluded. We defined elevated Lp(a) as ≥50 mg/dL or ≥125 nmol/L and matched cohorts 1:1 by propensity score on demographics, comorbidities, medications, and BMI. The primary outcome was MACE (acute myocardial infarction [AMI], ischemic stroke, transient ischemic attack [TIA], or coronary revascularization). Secondary outcomes were the individual components of MACE, major adverse limb events (MALE), heart failure hospitalization, and all-cause mortality. We tested for a dose-response across Lp(a) quartiles and used lower extremity fracture and pneumonia as falsification endpoints. Results: Of 69,059 eligible patients, 41,750 were included after matching (20,875 per group; mean age, 61.7 years; 42.3% female; all SMDs <0.1). Over a median follow-up of 2.6 to 3.1 years, patients with elevated Lp(a) had higher rates of MACE (HR 1.08; 95% CI 1.04-1.12; P<.001), AMI (HR 1.19; 1.12-1.26), coronary revascularization (HR 1.24; 1.14-1.35), MALE (HR 1.43; 1.23-1.66), and heart failure hospitalization (HR 1.13; 1.05-1.22) (Figure 1). Stroke/TIA and all-cause mortality did not differ between groups. Risk rose stepwise across Lp(a) quartiles for MACE, AMI, coronary revascularization, and MALE (Figure 2). The association held in both the primary prevention (MACE HR 1.13; 1.09-1.18) and secondary prevention (MACE HR 1.07; 1.03-1.11) subgroups. Falsification endpoints did not differ between groups. Conclusions: In patients who reached LDL-C <70 mg/dL on statin and/or ezetimibe therapy, elevated Lp(a) was associated with higher rates of coronary and limb ischemic events and heart failure hospitalization, with a graded dose-response across Lp(a) levels and consistent signals in primary and secondary prevention. These data support routine Lp(a) measurement and identify a population with controlled LDL-C but elevated Lp(a) as a high-yield target for emerging Lp(a)-lowering therapies to address residual risk.