Association of Lipoprotein(a) With Major Adverse Cardiovascular Events Across hs-CRP: A Systematic Review and Meta-Analysis

Abstract

Background: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. The relationship between Lp(a) and major adverse cardiovascular events (MACE) in the context of high-sensitivity C-reactive protein (hs-CRP) levels remains controversial due to conflicting results from previous studies.

Objectives: This systematic review and meta-analysis aimed to clarify the association between Lp(a) and risk of MACE across different hs-CRP levels in both primary and secondary prevention settings.

Methods: We performed a systematic review by searching MEDLINE (PubMed), Embase (Ovid), Cochrane CENTRAL (Wiley), and Web of Science (Clarivate) from their inception to February 2024. Eligible studies reported the association of Lp(a) with MACE stratified by hs-CRP level. Data extraction and quality assessment were systematically conducted. Meta-analyses used random-effects models to compute pooled HRs for individuals with low (<2 mg/L) and high (≥2 mg/L) hs-CRP levels. Subgroup analyses were performed in primary and secondary prevention populations.

Results: Nine publications encompassing 11 studies that involved 562,301 participants met the inclusion criteria. The mean proportion of females was 39.9% and the weighted mean age for the entire cohort was 61.2 years. Elevated Lp(a) was significantly associated with MACE risk in both low and high hs-CRP groups, with pooled HR of 1.26 (95% CI: 1.11-1.42) and 1.33 (95% CI: 1.20-1.47), respectively. In the primary prevention group, the pooled HR for low and high hs-CRP groups was 1.33 (95% CI: 1.06-1.66) and 1.43 (95% CI: 1.13-1.82), respectively (subgroup difference, P = 0.65). The corresponding HRs for the secondary prevention population were 1.13 (95% CI: 1.00-1.27) and 1.31 (95% CI: 1.12-1.52), respectively (subgroup difference P = 0.13).

Conclusion: Elevated Lp(a) is associated with an increased risk of MACE independent of hs-CRP levels in both primary and secondary prevention populations.

Keywords: Lp(a); cardiovascular outcomes; inflammation.

Graphical abstract

Figure 1

PRISMA Flow Diagram for Study Selection Process This PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram outlines the study selection process for our systematic review and meta-analysis assessing the association between Lipoprotein(a) [Lp(a)] and major adverse cardiovascular events (MACE) across varying levels of high-sensitivity C-reactive protein (hs-CRP). Initially, 1,425 studies were identified from databases including PubMed, Embase, Cochrane, and Web of Science. After rigorous screening and eligibility assessment, eleven studies from nine publications comprising 562,301 participants were included in the final analysis. Names of the databases searched: PubMed, Embase, Cochrane, Web of Science. hs-CRP = high-sensitivity C-reactive protein; Lp(a): lipoprotein(a); MACE = major adverse cardiovascular events; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2

Pooled HRs for the Association Between Lipoprotein(a) and MACE Across Low and High hs-CRP Groups Forest plots illustrating the pooled HRs for the association between elevated Lipoprotein(a) [Lp(a)] levels and major adverse cardiovascular events (MACE) in both low hs-CRP (<2 mg/L) and high hs-CRP (≥2 mg/L) groups. This meta-analysis includes data from eleven studies with various populations, reflecting significant heterogeneity (I² = 88% for low hs-CRP and I² = 86% for high hs-CRP). The HRs are stratified by hs-CRP levels to demonstrate the differential impact of inflammation on the cardiovascular risk posed by elevated Lp(a) levels. Elevated Lp(a) was significantly associated with MACE risk across low and high hs-CRP groups, with pooled HR of 1.26 (95% CI: 1.11–1.42) and 1.33 (95% CI: 1.20–1.47), respectively. hs-CRP = high-sensitivity C-reactive protein; IV = inverse variance; Lp(a) = lipoprotein(a); MACE = major adverse cardiovascular events; SE = standard error.

Figure 3

Pooled HRs for the Association Between Lipoprotein(a) and MACE Stratified by hs-CRP Levels in Primary and Secondary Prevention Populations The pooled HRs demonstrating the association of lipoprotein(a) [Lp(a)] with major adverse cardiovascular events (MACE) across different hs-CRP levels, categorized into primary and secondary prevention groups. The forest plots show HRs for low (<2 mg/L) and high (≥2 mg/L) hs-CRP conditions in primary and secondary prevention settings. In the primary prevention group, the pooled HR for low and high hs-CRP groups was 1.33 (95% CI: 1.06–1.66) and 1.43 (95% CI: 1.13–1.82), respectively (subgroup difference, p = 0.65). The corresponding HRs for the secondary prevention population was 1.13 (95% CI: 1.00–1.27) and 1.31 (95% CI: 1.12–1.52), respectively (subgroup difference p = 0.13). There was no significant difference between primary and secondary prevention populations, indicating a consistent influence of Lp(a) across various clinical contexts. hs-CRP = high-sensitivity C-reactive protein; IV = inverse variance; Lp(a) = lipoprotein(a); MACE = major adverse cardiovascular events.

Central Illustration

Association of Lipoprotein(a) Levels on Major Adverse Cardiovascular Events Across hs-CRP Levels The pooled HRs for the association between elevated Lipoprotein(a) [Lp(a)] levels and the risk of major adverse cardiovascular events (MACE) stratified by high-sensitivity C-reactive protein (hs-CRP) levels are illustrated. Data were pooled from 562,301 individuals participating in eleven large studies including primary and secondary prevention cohorts. The figure shows that elevated Lp(a) levels are associated with an increased risk of MACE across both low (<2 mg/L) and high (≥2 mg/L) hs-CRP levels. Subgroup analyses in primary and secondary prevention populations further detail the consistent risk elevation across different hs-CRP strata. Studies: UK Biobank, MESA(Multi-Ethnic Study of Atherosclerosis), Copenhagen General Population Study, FOURIER-TIMI 59 (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes), BiomaCARE (Biomarker for Cardiovascular Risk Assessment in Europe), REGARDS (REasons for Geographic and Racial Differences in Stroke), CRIC (The Chronic Renal Insufficiency Cohort) and 2 cohorts from Fuwai Hospital, Beijing, China. IV = inverse variance; Lp(a) = lipoprotein(a); MACE = major adverse cardiovascular events.