Abstract Body (Do not enter title and authors here): Background: High levels of small dense low-density lipoprotein (sdLDL) is a hallmark of dyslipidemia; however, studies on sdLDL cholesterol levels and risk of peripheral artery disease are sparse and results inconclusive.

Hypothesis: We tested the hypothesis that higher levels of sdLDL cholesterol are associated with increased risk of peripheral artery disease in a primary prevention setting.

Methods: We studied 31,036 individuals free of lipid-lowering therapy, ischemic stroke, and myocardial infarction at study entry in 2013-2017. All had fresh sample measurements of sdLDL cholesterol. During a median follow-up on 6.2 years, 155 were diagnosed with peripheral artery disease. The association was confirmed using ankle-brachial index (ABI) ≤ 0.9 as endpoint. Lastly, as comparison across different vascular beds risk estimates for myocardial infarction and ischemic stroke were calculated.

Results: Higher levels of sdLDL cholesterol were associated with higher risk of peripheral artery disease and an ABI ≤ 0.9 illustrated by cubic splines multivariable adjusted for sex, systolic blood pressure, education, body mass index (BMI), diabetes, large buoyant LDL cholesterol, and age. Per 1 mmol/L (37 mg/dL) higher sdLDL cholesterol hazard ratio for peripheral artery disease was 2.01 (95% CI: 1.41-2.85) and odds ratio for an ABI ≤ 0.9 was 1.51 (95% CI: 1.07-2.14) in multivariable adjusted models. The cumulative incidence of peripheral artery disease was respectively 1.5%, 2.5%, and 3.5% for individuals having a sdLDL cholesterol in the 1^st-50^th, 51^st-90^th, and the 91^st-100^th percentiles at age 80. For the 91^st-100^th versus the 1^st-50^th percentile a hazard ratio on 2.51 (95% CI: 1.50-4.20) for peripheral artery disease, 2.18 (95% CI: 1.58-3.01) for myocardial infarction, and 1.85 (95% CI: 1.37-2.49) for ischemic stroke was found. Furthermore, the association of higher sdLDL cholesterol with increased risk of peripheral artery disease was robust in sensitivity analyses.

Conclusion: Higher levels of sdLDL cholesterol were robustly associated with increased risk of peripheral artery disease in a primary prevention setting.