Lipoprotein(a) identifies premature coronary artery disease in patients with low LDL-cholesterol: A large multicenter cohort study.

Abstract

Background: Lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for atherosclerotic cardiovascular disease. Whether elevated Lp(a) is associated with premature coronary artery disease (pCAD) in young and middle-aged adults with low levels of low-density lipoprotein cholesterol (LDL-C) remains poorly characterized in real-world practice.

Objective: To assess the association between elevated Lp(a) (≥50 mg/dL) and incident pCAD after comprehensive lipid adjustment, including among patients with LDL-C <100 mg/dL.

Methods: We conducted a retrospective cohort study across 3 Mayo Clinic sites of adults without prior CAD (males 18-50 years; females 18-60 years) who underwent Lp(a) testing (enrollment 2000-2020; follow-up through 2024). The exposure was Lp(a) ≥50 mg/dL; the outcome was incident pCAD. Multivariable Cox models were adjusted for LDL-C, high-density lipoprotein cholesterol, triglycerides, and standard risk factors, with competing-risk, multiple-imputation, and prespecified sensitivity analyses, including patients with LDL-C <100 mg/dL.

Results: Among 35,622 patients (55.9% female; median age 46 years), 459 (1.3%) developed pCAD over a median of 6.0 years (incidence rate 1.85 per 1000 person-years; 95% CI, 1.69-2.03). Elevated Lp(a) was independently associated with pCAD (adjusted hazard ratio [HR] 1.40; 95% CI 1.12-1.74; P = .003), with a log-linear dose-response. The association did not weaken when LDL-C was low: among 10,949 patients with LDL-C <100 mg/dL, elevated Lp(a) carried a 67% higher adjusted risk (HR 1.67; 95% CI 1.15-2.43; P = .007). The Lp(a) × LDL-C interaction was nonsignificant (P = .571), indicating the effect was undiminished rather than amplified by low LDL-C.

Conclusion: In young and middle-aged adults with low LDL-C, elevated Lp(a) is significantly associated with premature coronary risk that is not captured by conventional lipid panels. These real-world data support Lp(a) measurement at a younger age as a tool for individual risk reclassification, identifying patients who carry occult residual atherogenic risk and may benefit from emerging Lp(a)-targeted therapies.