Aspirin for primary prevention in patients with diabetes according to lipoprotein(a) levels: a real-world propensity-matched analysis

Background Aspirin may be considered for primary prevention in selected patients with diabetes mellitus (DM). Lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor linked to myocardial infarction and stroke and may promote thrombogenicity. Whether the association between aspirin use and cardiovascular outcomes differs according to Lp(a) levels remains uncertain. Purpose To evaluate the association between aspirin use and cardiovascular outcomes in primary prevention among patients with DM according to Lp(a) levels. Methods Retrospective cohort study using the TriNetX database. Adults with DM and Lp(a) measurements were included. Individuals with prior atherosclerotic cardiovascular disease (ASCVD) were excluded to restrict the analysis to primary prevention. Patients were stratified according to Lp(a) levels as normal (Lp(a) <50 mg/dL) or elevated (Lp(a) ≥50 mg/dL) and categorized as aspirin users or non-users based on prescription records within the first year after DM diagnosis. Follow-up started 366 days after DM diagnosis and continued for up to 5 years. Propensity score matching (1:1) balanced baseline characteristics between aspirin users and non-users in each group. The primary outcome was a composite of all-cause death, myocardial infarction, ischemic stroke. Secondary outcomes included individual components of primary outcome and major bleeding. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Interaction analysis assessed effect modification by Lp(a) levels. Results After matching, among patients with normal Lp(a), aspirin use was associated with a higher risk of the composite outcome (HR 1.31, 95%CI 1.05–1.63) and ischemic stroke (HR 1.53, 95%CI 1.14–2.05), with no significant differences in myocardial infarction, major bleeding, or all-cause death (Figure 1). Among patients with elevated Lp(a), no significant differences were found between aspirin use and non-use in the composite outcome or individual components (Figure 1). A higher risk of major bleeding (HR 1.70, 95% CI 1.11–2.62) was found in aspirin users compared to non-users. No significant interaction was observed between aspirin use and Lp(a) levels for the composite outcome (p-interaction = 0.33), myocardial infarction (p-interaction = 0.67), major bleeding (p-interaction = 0.37), or all-cause death (p-interaction = 0.85). A borderline interaction was observed for ischemic stroke (p-interaction = 0.05), with an increased risk among aspirin users in the normal Lp(a) group but not in those with elevated Lp(a) (Figure 1). Conclusion In this large real-world cohort of patients with DM, no significant interaction between Lp(a) status and aspirin use was observed for the primary outcome. These findings do not support a differential benefit of aspirin according to Lp(a) levels in patients with DM in the primary prevention settings.