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Background <p>Atherogenic lipid-related risk may not be fully characterized by a single lipid measure. A dual-axis framework combining apolipoprotein B (ApoB), a measure of atherogenic particle number, with the LDL-C to total cholesterol ratio (LDL-C/TC), a derived measure of cholesterol partitioning, has been proposed to characterize lipid-related risk heterogeneity. The position of remnant cholesterol (RC) within this framework remains uncertain.</p> Methods <p>We analyzed 288,257 UK Biobank participants free of cardiovascular disease and lipid-lowering therapy. Participants were classified using dual-axis framework. Associations with incident atherosclerotic cardiovascular disease (ASCVD) were assessed using Cox models. RC was evaluated in combination with these axes across strata, including SCORE2-defined low-to-intermediate risk populations.</p> Results <p>Over a median follow-up of 13.9&#xa0;years, the dual-axis framework differentiated ASCVD risk, with the dual-elevated phenotype (ApoB ≥ 90&#xa0;mg/dL and LDL-C/TC ≥ 0.60) showing the highest risk (adjusted hazard ratio 1.23; 95% CI, 1.17–1.29). RC did not modify associations across dual-axis categories (<i>P</i> for interactio<i>n</i> = 0.44), and higher RC levels were associated with attenuation of risk gradients across categories. In low-to-intermediate SCORE2 risk individuals, increasing numbers of elevated markers (ApoB, LDL-C/TC ratio, and RC) were associated with stepwise increases in risk, with absolute risk differences reaching 1.49% at 10&#xa0;years for individuals with all three markers elevated versus those with none elevated. ApoB and the LDL-C/TC ratio produced small C-index increases (ΔC, 0.0013 and 0.0012), whereas RC produced no further improvement (ΔC, − 0.0001; <i>P</i> = 0.364).</p> Conclusions <p>RC did not materially modify associations across ApoB–LDL-C/TC phenotypes but identified absolute-risk heterogeneity within ApoB strata. Co-occurring marker elevations characterized higher-risk lipid phenotypes, although gains in discrimination were small and require external validation.</p> Graphical Abstract <p></p>

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Remnant cholesterol–incorporating dual-axis lipid risk stratification using apolipoprotein B and the LDL-C to total cholesterol ratio: a prospective cohort study from the UK Biobank

  • 期刊论文

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  • 发表日期：

    2026年8月5日

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  • Bin Wang,
  • Dong Li

摘要

Background

Atherogenic lipid-related risk may not be fully characterized by a single lipid measure. A dual-axis framework combining apolipoprotein B (ApoB), a measure of atherogenic particle number, with the LDL-C to total cholesterol ratio (LDL-C/TC), a derived measure of cholesterol partitioning, has been proposed to characterize lipid-related risk heterogeneity. The position of remnant cholesterol (RC) within this framework remains uncertain.

Methods

We analyzed 288,257 UK Biobank participants free of cardiovascular disease and lipid-lowering therapy. Participants were classified using dual-axis framework. Associations with incident atherosclerotic cardiovascular disease (ASCVD) were assessed using Cox models. RC was evaluated in combination with these axes across strata, including SCORE2-defined low-to-intermediate risk populations.

Results

Over a median follow-up of 13.9 years, the dual-axis framework differentiated ASCVD risk, with the dual-elevated phenotype (ApoB ≥ 90 mg/dL and LDL-C/TC ≥ 0.60) showing the highest risk (adjusted hazard ratio 1.23; 95% CI, 1.17–1.29). RC did not modify associations across dual-axis categories (P for interaction = 0.44), and higher RC levels were associated with attenuation of risk gradients across categories. In low-to-intermediate SCORE2 risk individuals, increasing numbers of elevated markers (ApoB, LDL-C/TC ratio, and RC) were associated with stepwise increases in risk, with absolute risk differences reaching 1.49% at 10 years for individuals with all three markers elevated versus those with none elevated. ApoB and the LDL-C/TC ratio produced small C-index increases (ΔC, 0.0013 and 0.0012), whereas RC produced no further improvement (ΔC, − 0.0001; P = 0.364).

Conclusions

RC did not materially modify associations across ApoB–LDL-C/TC phenotypes but identified absolute-risk heterogeneity within ApoB strata. Co-occurring marker elevations characterized higher-risk lipid phenotypes, although gains in discrimination were small and require external validation.

Graphical Abstract