Apolipoprotein B beyond LDL-cholesterol in predicting Atherosclerotic Cardiovascular Disease risk in high-risk populations
S Demeester, A Misra, S Haidermota, W Hornsby, M C Honigberg, P Natarajan, A P PatelAbstract
Background
Despite achieving target low-density lipoprotein cholesterol (LDL-C) levels, many individuals remain at elevated atherosclerotic cardiovascular disease (ASCVD) risk. Apolipoprotein B (ApoB), reflecting atherogenic particle number instead of cholesterol mass, may better capture this residual risk.
Purpose
To investigate ApoB’s predictive value beyond LDL-C for ASCVD in high-risk groups with controlled LDL-C.
Methods
We analyzed UK Biobank individuals without pre-existing ASCVD and with controlled LDL-C (<100 mg/dL, Sampson equation), categorized into distinct clinical subgroups: no other risk-enhancing factors (REFs), high polygenic risk score (PRS, top quintile) for coronary artery disease (CAD), CAD family history, metabolic syndrome, high triglycerides (≥175 mg/dL), high C-reactive protein (CRP; 2-10 mg/L), chronic kidney disease, chronic inflammatory conditions (psoriasis, lupus erythematosus, rheumatoid arthritis or human immunodeficiency virus infection), female reproductive risk factors (hypertensive disorders of pregnancy or early menopause, age <45 years), South Asian ethnicity and high lipoprotein(a) (Lp(a); ≥125 nmol/L). Poisson models were adjusted for age, sex, Lp(a), lipid-lowering medication and the first ten principal components of genetic ancestry. We calculated incident ASCVD rates, comparing those with high (≥80 mg/dL) vs. low ApoB and reported Benjamini-Hochberg corrected p-values.
Results
Among 61,376 individuals without pre-existing ASCVD and with controlled LDL-C (54.6% male, mean age 57.5 (SD 8.6) years), the overall ASCVD incidence rate was 7.31/1,000 person-years (PY). High ApoB was associated with increased ASCVD risk (IR 1.80 vs. 1.17/1,000 PY, ΔIR 0.63, p=0.045) in individuals with no other REF (n=8,459). This association was more pronounced in established high-risk groups of participants with elevated triglycerides (IR 8.91 vs. 7.51/1,000 PY, ΔIR 1.40, p<0.001) and metabolic syndrome (IR 10.70 vs. 9.59/1,000 PY, ΔIR 1.11, p=0.018). Additionally, high ApoB showed predictive value in individuals with high PRS (IR 12.81 vs. 10.58/1,000 PY, ΔIR 2.23, p=0.004), CAD family history (IR 9.12 vs. 7.35/1,000 PY, ΔIR 1.77, p<0.001), and high CRP (IR 8.65 vs. 6.89/1,000 PY, ΔIR 1.76, p<0.001). No significant increased risk was observed in individuals with chronic kidney disease, chronic inflammatory conditions, high Lp(a), female reproductive risk factors, or South Asian ethnicity (all p>0.05).
Conclusion
ApoB enhances ASCVD risk stratification in higher-risk subgroups with controlled LDL-C. While ApoB’s role in metabolic syndrome and hypertriglyceridemia is established, we show additional predictive value for those with high polygenic risk, elevated CRP, or CAD family history. Findings support using ApoB to refine risk assessment and guide treatment intensification for selected high-risk populations despite controlled LDL-C.