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

Abstract

Abstract 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.