Single LDL-c, hs-CRP, and Lp(a) measurement predicts long-term MACE risk in healthy Europeans

An EPIC-Norfolk study analysis showed one-time screening of LDL-c, hs-CRP, and Lp(a) predicted the risk of incident MACE over 20 years in a European primary prevention population.

This summary is based on the publication of Kraaijenhof JM, Nurmohamed NS, Nordestgaard AT, et al. - Low-density lipoprotein cholesterol, C-reactive protein, and lipoprotein(a) universal one-time screening in primary prevention: the EPIC-Norfolk study. Eur Heart J. 2025 Apr 1:ehaf209 [Online ahead of print]. doi: 10.1093/eurheartj/ehaf209.

Introduction and methods

Background

Recently, the prospective Women’s Health Study among initially healthy American women demonstrated that a single measurement of LDL-c, hs-CRP, and Lp(a) strongly predicted future CV events over 30 years [1]. These biomarkers, both independently and in combination, identified distinct risk patterns in individual patients that would not have been detected using traditional prediction algorithms. However, before universal one-time screening of these 3 biomarkers can be used in primary prevention, external replication to ensure consistency, validity, and generalizability is required.

Aim of the study

The authors examined the associations of LDL-c, hs-CRP, and Lp(a) levels, both individually and in combination, with the long-term risk of CV events in a European primary prevention population of women and men.

Methods

Data were collected from 17,087 initially healthy men and women who were enrolled in the prospective EPIC (European Prospective Investigation into Cancer) Norfolk study in the period 1993–1997 and who had available LDL-c, hs-CRP, and Lp(a) measurements at study entry [2,3]. Median follow-up duration was 20.5 years (IQR: 19.6–21.5).

Outcome

The endpoint was a composite outcome of first MACE, defined as (fatal or nonfatal) coronary artery disease or (fatal or nonfatal) ischemic stroke.

Main results

Individual associations of biomarkers with MACE incidence

• The cumulative incidence of MACE increased with increasing baseline levels of the biomarkers. In a multivariable-adjusted analysis comparing quintile 5 of each baseline biomarker level with quintile 1, the HR was 1.78 (95%CI: 1.57–2.00) for LDL-c, 1.55 (95%CI: 1.37–1.74) for hs-CRP, and 1.19 (95%CI: 1.07–1.33) for Lp(a).
• Sex-stratified analyses showed the risk of incident MACE associated with the 3 biomarkers was generally lower in women than men. When comparing quintile 1 with quintile 5, the multivariable-adjusted HR for LDL-c was 1.46 (95%CI: 1.21–1.75) in women and 1.91 (95%CI: 1.63–2.23) in men; for hs-CRP, it was 1.37 (95%CI: 1.15–1.63) in women and 1.75 (95%CI: 1.49–2.06) in men; and for Lp(a), it was 1.13 (95%CI: 0.96–1.32) in women and 1.26 (95%CI: 1.09–1.46) in men.

Combined association of biomarkers with MACE incidence

• Participants with 1 biomarker in quintile 5 had an elevated MACE risk compared with those with no biomarker in quintile 5 (adjusted HR: 1.33; 95%CI: 1.23–1.43). In individuals with 2 biomarkers in quintile 5, this risk was further increased (adjusted HR: 1.68; 95%CI: 1.51–1.87), whereas the highest risk was observed in those with all 3 biomarkers in quintile 5 (adjusted HR: 2.41; 95%CI: 1.90–3.07).
• Sex-stratified analyses demonstrated similar results.

Conclusion

In this analysis of the EPIC-Norfolk study cohort, a single combined measurement of LDL-c, hs-CRP, and Lp(a) levels predicted the risk of incident MACE over 20 years in initially healthy European men and women. Each biomarker contributed both individually and in combination to the MACE risk. The authors “believe the time has come for universal screening of these 3 biomarkers in primary as well as secondary prevention.”

Find this article online at Eur Heart J.

References

1. Ridker PM, Moorthy MV, Cook NR, Rifai N, Lee I-M, Buring JE. Inflammation, cholesterol, lipoprotein(a), and 30-year cardiovascular outcomes in women. N Engl J Med 2024;391:2087–97. https://doi.org/10.1056/NEJMoa2405182
2. Day N, Oakes S, Luben R, Khaw KT, Bingham S, Welch A, et al. EPIC-Norfolk: study design and characteristics of the cohort. Br J Cancer 1999;80:95–103. https://doi.org/10.1080/01621459.1999.10474144
3. Hayat SA, Luben R, Keevil VL, Moore S, Dalzell N, Bhaniani A, et al. Cohort profile: a prospective cohort study of objective physical and cognitive capability and visual health in an ageing population of men and women in Norfolk (EPIC-Norfolk 3). Int J Epidemiol 2014;43:1063–72. https://doi.org/10.1093/ije/dyt086