ELEVATED remnant cholesterol (RC) exerts a stronger independent causal effect on peripheral artery disease (PAD) than LDL cholesterol (LDL-C), with LDL-C’s impact largely dependent on coexisting RC elevations, according to a Mendelian randomization study of 796,722 individuals.
This study aimed to clarify the roles of RC and LDL-C in PAD, as both are known to increase coronary artery disease (CAD) risk. Researchers used genetic variants from UK Biobank data to construct scores for RC and LDL-C, employing univariable and multivariable Mendelian randomization to estimate their causal effects on PAD (38,414 cases) and CAD (221,445 cases).
The results showed that increments in RC and LDL-C genetic scores corresponding to 1 mmol/L (39 mg/dL) higher levels were associated with univariable odds ratios (ORs) for PAD of 2.72 (95% CI: 2.10–3.52) for RC and 1.37 (95% CI: 1.25–1.51) for LDL-C. The multivariable ORs were 2.16 for RC and 1.14 for LDL-C. For CAD, the univariable ORs were 2.92 for RC and 1.67 for LDL-C, with multivariable ORs of 1.86 for RC and 1.44 for LDL-C. Scaled to 1 SD increments, RC showed stronger independent effects on PAD (OR: 1.28) than LDL-C (OR: 1.11), while LDL-C had greater CAD impact (OR: 1.34 vs. RC: 1.22).
These findings indicate that RC is the primary cholesterol fraction driving PAD risk, with LDL-C’s effects largely contingent on concurrent RC elevation. In contrast, both RC and LDL-C independently contribute to CAD. The results suggest that RC-lowering therapies (e.g., fibrates, PCSK9 inhibitors) may be critical for PAD prevention, while LDL-C remains a key CAD target. Clinical guidelines should prioritize RC management in high-risk PAD populations, and trials should explore RC-specific interventions.
Reference
Wadström BN et al. Elevated remnant and LDL cholesterol and the risk of peripheral artery disease: a mendelian randomization study. JACC. 2025;85(12):1353-68.
