Protective Role of High-Density Lipoprotein Cholesterol in Stress Urinary Incontinence with Special Emphasis on Overweight/Obese Individuals

<b>Background:</b> Increasing evidence shows that lipid metabolism is closely related to the pathogenesis of stress urinary incontinence (SUI). This study aimed to investigate the association between high-density lipoprotein cholesterol (HDL-C) levels and female SUI, evaluate dose-response relationships, and determine the causal effect of HDL-C on SUI risk. <b>Materials and methods:</b> Utilizing cross-sectional data from the National Health and Nutrition Examination Survey (2001-2020, n = 18,415), we assessed the dose-response relationship between HDL-C and SUI using restricted cubic splines and weighted logistic regression. Mendelian randomization (MR) analyses leveraged genetic instruments from European cohorts (HDL-C: n = 9,796; SUI: 5,926 cases/211,672 controls) to infer causality. Subgroup analyses emphasized interactions between HDL-C and BMI. <b>Results:</b> A 1 mg/dL increase in HDL-C was linearly associated with a 0.5% reduction in SUI risk (OR = 0.995, 95% CI: 0.986-0.991, <i>P</i> < 0.001). Participants in the highest HDL-C quartile (Q4) exhibited a 25.1% lower SUI risk compared to Q1 (OR = 0.749, 95% CI: 0.652-0.859). Notably, the protective effect of HDL-C was markedly stronger in overweight/obese individuals (BMI ≥ 25 kg/m²: OR = 0.992, <i>P</i> = 0.006; BMI ≥ 30 kg/m²: OR = 0.991, <i>P</i> = 0.001), with significant interaction (<i>P</i> for interaction = 0.015). MR analyses confirmed a causal protective effect of HDL-C on SUI (IVW OR = 0.842, 95% CI: 0.744-0.953), and sensitivity analyses supported robustness. <b>Conclusions:</b> Elevated HDL-C levels are causally linked to reduced SUI risk, with amplified protection in overweight/obese populations. These findings highlight the importance of maintaining healthy HDL-C levels as a targeted strategy for SUI prevention, especially in high-BMI individuals.