Introduction: Lipoprotein(a) Lp(a) is an established independent risk factor for atherosclerotic cardiovascular disease (ASCVD), but its impact among statin-naive individuals with optimal low-density lipoprotein cholesterol (LDL-C) levels remains uncertain. As emerging Lp(a)-lowering therapies target residual cardiovascular risk, clarifying the contribution of Lp(a) at optimal LDL-C levels is clinically relevant. Methods: We used the TriNetX U.S. Collaborative Network (2015–2025; 87 health systems) to identify adults aged 18–75 years with measured Lp(a) and an LDL-C level of ≤70 mg/dL. Patients were classified into two cohorts based on Lp(a) level. Elevated Lp(a) was defined as ≥50 mg/dL (≥125 nmol/L), and non-elevated as ≤49 mg/dL (≤124 nmol/L). Patients with prior lipid-lowering therapy (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, alirocumab, evolocumab, or inclisiran) or preexisting ASCVD, including acute coronary syndrome (ACS), cerebrovascular accident (CVA), transient ischemic attack (TIA), or peripheral artery disease (PAD), were excluded. We used 1:1 greedy nearest-neighbor propensity-score matching to balance baseline characteristics by demographics, tobacco use, blood pressure, and hemoglobin A1c. The primary outcome was the incidence of ASCVD (a composite of ACS, CVA/TIA, and PAD) over a longitudinal follow-up period of up to 20 years; secondary outcomes included the individual components of the composite outcome. Results: Among 19,204 total patients, 4,177 had elevated Lp(a) and 15,027 had non-elevated Lp(a) levels. After matching, 4,176 patients remained in each group with balanced baseline characteristics. No significant differences were observed in cumulative ASCVD risk between groups (11.4% vs 11.0%; risk ratio RR 1.04, 95% CI 0.92–1.17; p =0.58). Rates of individual outcomes were similar for ACS (4.8% vs 4.0%; RR 1.20, 95% CI 0.98–1.46; p =0.08), CVA/TIA (5.0% vs 5.2%; RR 0.97, 95% CI 0.81–1.17; p =0.76), and PAD (3.8% vs 3.8%; RR 1.01, 95% CI 0.82–1.26; p =0.91). Conclusion: In a retrospective cohort of statin-naive adults with optimal LDL-C levels (≤70 mg/dL), elevated Lp(a) was not significantly associated with increased long-term risk of ASCVD. These findings suggest that at optimal LDL-C levels, the contribution of Lp(a) to residual ASCVD risk may be attenuated. Future studies should evaluate whether targeted Lp(a)-lowering therapies can further reduce risk in such populations.
Kothari et al. (Tue,) studied this question.
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