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. 2025 Jun 12:zwaf340.
doi: 10.1093/eurjpc/zwaf340. Online ahead of print.

Lipoprotein (a) and Incident Coronary Heart Disease in the Community: Impact of Traditional Cardiovascular Risk Factors

Natalie Arnold  1   2   3 , Alina Goßling  1   3 , Benjamin Bay  1   2   3 , Jessica Weimann  1   3 , Christopher Blaum  1   3 , Fabian J Brunner  1   2   3 , Marco M Ferrario  4 , Paolo Brambilla  5 , Giancarlo Cesana  5 , Valerio Leoni  6 , Luigi Palmieri  7 , Chiara Donfrancesco  7 , Teresa Padró  8   9 , Jonas Andersson  10 , Pekka Jousilahti  11 , Francisco Ojeda  1   3 , Tanja Zeller  12   2   3 , Allan Linneberg  13   14 , Stefan Söderberg  15 , Licia Iacoviello  16   17 , Francesco Gianfagna  4   18 , Susana Sans  19 , Giovanni Veronesi  4 , Barbara Thorand  20   21 , Annette Peters  20   21   22 , Hugh Tunstall-Pedoe  23 , Frank Kee  24 , Veikko Salomaa  11 , Renate B Schnabel  1   2   3 , Kari Kuulasmaa  11 , Stefan Blankenberg  1   2   3 , Christoph Waldeyer  1   2   3 , Wolfgang Koenig  22   25   26
Affiliations

Lipoprotein (a) and Incident Coronary Heart Disease in the Community: Impact of Traditional Cardiovascular Risk Factors

Natalie Arnold et al. Eur J Prev Cardiol. .

Abstract

Aims: Deleterious effects Lipoprotein (a) (Lp(a)) might be mitigated by overall cardiovascular (CV) risk reduction. However, data on the relationship between increased Lp(a) and incident coronary heart disease (CHD) according to the distribution of modifiable CV risk factors (CVRF) at baseline are still scarce. We investigated the association between high Lp(a) and incident CHD in the general population, depending on the presence/absence of four major CVRFs (hypertension, diabetes, hypercholesterolemia, smoking) at baseline.

Methods: Overall 66,495 CHD-free individuals from eight European prospective population-based cohorts were included. The cohort was stratified according to CVRF burden at baseline in "0/1 CVRF" (low risk; n= 41,770) and"≥2 CVRFs" (increased risk; n=24,725). Fine and Gray competing risk-adjusted models were calculated for the association between Lp(a) mass (<90th versus ≥90th percentile (pctl.); cut-off 43.2 mg/dL) and future CHD events.

Results: During a median follow-up of 9.7 years, 3,467 incident CHD events occurred. Despite being at very low absolute risk based on traditional CVRF, individuals with 0/1CVRF demonstrated a strong association between increased Lp(a) mass (≥90th pctl.) and future CHD events, which was comparable to the association observed among individuals with ≥2 CVRFs. The fully-adjusted sub-distribution Hazard Ratios [sHRs] for elevated Lp(a) were 1.38 (95% CI, 1.12-1.71) versus 1.27 (95% CI, 1.10-1.46) in those having 0/1 versus ≥2 CVRFs at baseline (Pinteraction0.50).

Conclusion: Among CHD-free subjects, high Lp(a) was related to adverse outcome even in individuals with no or only one CVRF at baseline, thereby generating substantial challenges in mitigating Lp(a)-associated CHD risk in very low risk populations.

Keywords: Lipoprotein (a); general population; incident coronary heart disease; primary prevention; traditional modifiable risk factors.

Plain language summary

While therapeutic options for high Lipoprotein (a) (Lp(a)) are currently under investigation, the only possibility to mitigate the deleterious effects of a high Lp(a) level to date is through sufficient reduction of traditional cardiovascular risk factor (CVRF) burden. However, there are still uncertainties whether Lp(a)-related CV risk might differ between lower- and higher-risk individuals in the primary prevention setting. Therefore, the aim of the present analysis was to investigate whether the presence of classical CVRFs at baseline might affect the association between increased Lp(a) values and incident coronary heart disease (CHD) among subjects from the general population, who were free of CHD at time of enrollment.The study population, comprising 66,495 subjects from eight population-based cohorts, participating in the BiomarCaRE consortium was stratified for this analysis according to CVRF burden at baseline in “0/1 CVRF” (low risk; n= 41,770) and”≥2 CVRFs” (increased risk; n=24,725).Increased Lp(a) concentrations (i.e. being ≥ 90th pctl. of Lp(a) distribution) were associated with incident CHD independently of absolute baseline risk. Similar risk estimates have been found in individuals at very low absolute risk, having no or only one CVRF at baseline and those at elevated absolute risk with two or more traditional modifiable CVRFs.Our findings not only highlight substantial challenges in mitigating Lp(a)-associated CHD risk in very low risk populations but also underscore the unmet need for upcoming Lp(a)-targeting compounds in the primary prevention setting.

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