Cumulative non-high-density lipoprotein cholesterol exposure and residual cardiovascular mortality risk in patients with peripheral artery disease

Background Individuals with peripheral artery disease (PAD) face substantial residual cardiovascular risk despite lipid-lowering therapy. Non-high-density lipoprotein cholesterol (non-HDL-C) has been recognized as a more comprehensive marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C), but its prognostic value in PAD and the relevance of cumulative exposure remain unclear. This study investigated whether early cumulative non-HDL-C exposure is associated with cardiovascular death (CV death) in PAD and whether the same association is observed among individuals whose LDL-C is already well controlled. Methods A territory-wide PAD cohort in Hong Kong was analyzed. Early cumulative non-HDL-C and LDL-C exposures were defined as the lipid burden during the first 2 years after PAD diagnosis and were estimated using spline models. In the overall cohort, Fine-Gray competing-risk models were applied to assess the associations between tertiles of cumulative non-HDL-C exposure and CV death, with non-cardiovascular mortality treated as a competing event. Discordance analyses compared CV death risk across nine strata defined by cross-classified tertiles of cumulative LDL-C and non-HDL-C, with the low-LDL-C/low-non-HDL-C stratum as the reference. In the well-controlled LDL-C subgroup, the same competing risk framework was used to assess the residual risk of CV death across cumulative non-HDL-C categories. Results Among 3,847 patients, 637 CV deaths occurred during a mean follow-up of 7.30 ± 3.92 years. Higher cumulative non-HDL-C exposure was associated with a higher risk of CV death (subdistribution hazard ratio [SHR], 1.36; 95% confidence interval [CI], 1.11–1.65; P = 0.002). Notably, patients with high non-HDL-C despite low LDL-C showed higher CV death risk (SHR, 2.00; 95% CI, 1.12–3.57; P = 0.018). In the 516 individuals with well-controlled LDL-C, higher cumulative exposure of non-HDL-C remained significantly related to CV death risk (SHR, 2.68; 95% CI, 1.39–5.16; P = 0.003). Conclusions Higher early cumulative non-HDL-C exposure was associated with a higher risk of CV death in PAD, including individuals who had attained the LDL-C target. Incorporating non-HDL-C into routine lipid follow-up may help identify residual cardiovascular risk, improve risk stratification, and support secondary prevention in patients with PAD, thereby addressing the long-term cardiovascular burden in this population.