Key result
Direct Lp(a)-C measurement yields significantly lower levels than formula-based estimation methods.
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Why the study?
Formula-based approaches to estimate Lp(a)-C and corrected LDL-C rely on fixed assumptions that may not reflect Lp(a) heterogeneity, potentially biasing LDL-C target interpretation.
Does direct measurement of Lp(a)-C compared to formula-based approaches prevent the overestimation of Lp(a)-C and underestimation of corrected LDL-C in patients with elevated Lp(a)?
Observational (n=372)
Does direct measurement of Lp(a)-C compared to formula-based approaches prevent the overestimation of Lp(a)-C and underestimation of corrected LDL-C in patients with elevated Lp(a)?
p-value: p=<.001
Fixed-assumption formula-based corrections systematically overestimate Lp(a)-C and underestimate true LDL-C compared to direct measurement, which may inappropriately influence target attainment in patients requiring ultralow LDL-C levels.
Direct Lp(a)-C measurement may better capture heterogeneity than formulas; leaves open whether LDL-Ccorr refines risk stratification in practice.
BACKGROUND Measured low-density lipoprotein cholesterol (LDL-C) includes cholesterol carried by lipoprotein(a) [Lp(a)-C]. Formula-based approaches are used to estimate Lp(a)-C and derive LDL-C corrected for Lp(a)-C (LDL-Ccorr) but rely on fixed compositional assumptions that may not reflect Lp(a) heterogeneity. OBJECTIVE To compare direct measurement of Lp(a)-C with formula-based approaches for estimating Lp(a)-C and corrected LDL-C across a wide range of Lp(a) concentrations. METHODS We compared directly measured Lp(a)-C using an immunocapture-based assay (Direct Lp(a)-C) with 2 commonly used formula-based approaches (Rosenson-Marcovina [RM] and Dahlén [D]) in 2 independent cohorts spanning a broad range of Lp(a) concentrations: an elevated Lp(a) cohort (n = 278) in stable subjects and a community-based cohort (n = 94). LDL-Ccorr was calculated by subtracting Lp(a)-C from measured LDL-C using a direct assay. Apolipoprotein(a) [apo(a)] isoform size was determined in the community cohort. RESULTS In the elevated Lp(a) cohort (mean Lp(a) 250.8 nmol/L), Direct Lp(a)-C was 14.9 ± 6.0 mg/dL vs 19.3 ± 8.3 mg/dL and 35.4 ± 14.8 mg/dL using RM and D methods (P < .001). Corresponding LDL-Ccorr values were 62.6 ± 30.9 mg/dL (direct), 58.2 ± 33.0 mg/dL, and 42.5 ± 34.7 mg/dL (P < .001). Formula-based correction produced negative LDL-Ccorr values in up to 6.1% of participants. Across increasing Lp(a) strata, apolipoprotein B and measured LDL-C were stable, whereas formula-derived LDL-Ccorr declined significantly. Discordance increased with higher Lp(a)-C and was greatest among individuals with smaller apo(a) isoforms. CONCLUSION Fixed-assumption formula-based correction overestimates Lp(a)-C and underestimates LDL-derived cholesterol, particularly at elevated Lp(a) levels and across apo(a) isoform sizes. In the era of ultralow LDL-C targets, this systematic bias may influence LDL goal attainment. Direct measurement of Lp(a)-C provides an assay-based approach to assess LDL-derived cholesterol in elevated Lp(a).
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Tsimikas et al. (2026) conducted an observational in Elevated Lipoprotein(a) (n=372). Direct Lp(a)-C measurement vs. Formula-based approaches (Rosenson-Marcovina and Dahlén) was evaluated on Lp(a)-C concentration in the elevated Lp(a) cohort (p=<.001). Direct measurement of Lp(a)-C yielded significantly lower Lp(a)-C levels (14.9 mg/dL) than the Rosenson-Marcovina (19.3 mg/dL) and Dahlén (35.4 mg/dL) formula-based methods (P<0.001).
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