Abstract Body (Do not enter title and authors here): Background: Lipoprotein(a) [Lp(a)] is a known risk factor for atherosclerotic cardiovascular disease (ASCVD). However, it is unclear whether the ASCVD risk associated with elevated Lp(a) is uniform or differs according to baseline risk profiles.

Aims: To compare the association of elevated Lp(a) with incident ASCVD across levels of risk factor burden and 10-year predicted ASCVD risk.

Methods: We performed a prospective analysis among participants at Visit 4 (1996-98) of the ARIC study without baseline ASCVD and with Visit 4 Lp(a) measurements (Denka Seiken assay). ASCVD risk factors were smoking, hypercholesterolemia, diabetes, hypertension, and chronic kidney disease (CKD), and ASCVD risk was estimated using the PREVENT-ASCVD calculator. Elevated Lp(a) was defined as ≥30 mg/dL. We assessed the association of elevated Lp(a) with incident ASCVD events (nonfatal myocardial infarction, fatal coronary heart disease, or ischemic stroke) after Visit 4 through 12/31/22 with multivariable adjusted Cox proportional hazards models. Lp(a) associations were assessed for those with and without individual risk factors, by number of risk factors and at different levels of predicted ASCVD risk.

Results: Among 9,483 participants (mean age 63, 58% female, and 21% Black adults), there were 2,311 ASCVD events over a median 19.8 years of follow-up. Individuals with smoking, diabetes, hypertension, and CKD had nominally higher risk (HRs 1.3-1.4) associated with elevated Lp(a) than those without those conditions (HRs 1.1-1.2), with a significant interaction for diabetes (p=0.02) (Table 1). Higher risk in association with elevated Lp(a) was seen for those with a greater number of risk factors and with higher predicted ASCVD risk (Table 2). Elevated Lp(a) was associated with higher risk in those with 3-5 risk factors (HR 1.44 [95% 1.20-1.73]) than in those with 0-2 risk factors (HR 1.11 [95% CI: 1.00-1.23] p-interaction = 0.015). Similarly, elevated Lp(a) was associated with higher risk in those with ≥10% predicted risk (HR 1.42 [95% CI: 1.20-1.68]) than in those with <10% predicted risk (HR 1.11 [95% CI 1.00-1.24] p-interaction = 0.017).

Conclusions: Elevated Lp(a) has stronger ASCVD risk associations in those with a higher burden of clinical risk factors, especially diabetes. These finding suggest the importance of risk factor prevention and control for reducing Lp(a)-related risk and may help to inform the optimal targeting of emerging Lp(a) lowering therapies.