Intraindividual variability in lipoprotein(a): the value of a repeat measure for reclassifying individuals at intermediate-risk

Abstract Background Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease and outcomes. Levels are predominantly genetically determined and repeat measurements are traditionally considered unlikely to be useful. However, the temporal variation of Lp(a) is not well characterized and it is unclear whether a single measure of Lp(a) is sufficient to assess cardiovascular risk in all individuals. Purpose To determine the intraindividual variability of Lp(a) and whether a repeated measure reclassified Lp(a)-specific cardiovascular risk using the European Atherosclerosis Society (EAS) consensus statement risk categories. Methods This retrospective cohort study analyzed initial and repeated Lp(a) measures obtained using the same laboratory assay from 609 individuals in the Nashville Biosciences database accessed through the American Heart Association Precision Medicine Platform. Categorical variables are presented as counts (%) and compared using Fisher’s exact test. Continuous variables are presented as mean ± standard deviation or median (Q1-Q3), tested for normality using the Shapiro-Wilk test, and compared using parametric and nonparametric tests where appropriate. The Spearman’s Rank correlation coefficient was used to assess the relationship between two variables. The significance level was set at p<0.05. Results Median age was 52.5 (37.1-62.8) years, 45% were women, 80.3% were White patients, 13.3% were Black patients, 1.6% were Asian patients, and 4.8% were other/unknown patients. In terms of relevant comorbidities, 41% had ischemic heart disease, 24.1% had chronic kidney disease, and 13.5% had liver disease. The median time between the two Lp(a) measures was 1.07 (0.5-2.1) years. Our analysis shows a significant difference between the paired Lp(a) values (p<0.05), with 38.1% [95% CI 34.2%-42%] changing by ≥10mg/dL, and 40.5% [95%CI 36.6%-44.3%] changing by >25%. There was a positive correlation between the baseline Lp(a) levels and the absolute changes in Lp(a), (r=0.59, p<0.01). The proportions of individuals with variability are similar in those who were never on the potentially Lp(a)-altering agents (statin, niacin, or PCSK9 inhibitor drugs) (n=91), with 32% [95%CI 22.4%-41.6%] changing by ≥10mg/dL, and 34% [95%CI 24.3%-43.7%] changing by >25%. While over 90% of those whose values were initially in the EAS low-risk and high-risk categories remained in those categories, 53% of those in the intermediate "grey-zone" category transitioned to either the low (20%)- or the high (33%)- risk category (Figure). Conclusion(s) Temporal-related changes in Lp(a) variability were present in many individuals and should be included in calculating the expected effect sizes in future studies targeting Lp(a). A repeat Lp(a) measure may allow more precise Lp(a)-specific cardiovascular risk prediction for individuals whose initial value is in the EAS-defined intermediate "grey-zone" category.