Residual Risk From Remnant Cholesterol and Inflammation Despite Lipid‐Lowering Therapy and Association With Incident Peripheral Artery Disease in Type 2 Diabetes

Background Despite guideline‐recommended lipid‐lowering therapy, patients with type 2 diabetes retain a significant residual risk for peripheral artery disease (PAD). The contributions of remnant cholesterol (RC) and systemic inflammation in this treated population, particularly beyond achieved low‐density lipoprotein cholesterol, remain incompletely understood. Methods This prospective cohort study included 18 741 participants with type 2 diabetes from the UK Biobank who were free of PAD and were on lipid‐lowering therapy at baseline. Plasma RC and hsCRP (high‐sensitivity C‐reactive protein) levels were measured at baseline. Incident PAD was ascertained over a median follow‐up of 13.6 years. Multivariable Cox models were used to estimate hazard ratios after adjustment for demographic, clinical, metabolic, and treatment‐related covariates, including low‐density lipoprotein cholesterol and baseline coronary artery disease. Results During follow‐up, incident PAD occurred in 1223 participants (6.5%). Elevated RC and hsCRP levels were each independently linked to an increased risk of PAD. Participants with concurrent elevations in both RC and hsCRP exhibited the highest risk of incident PAD. These associations remained robust across multiple sensitivity analyses, including exclusion of participants with baseline coronary artery disease, removal of events within the initial 2‐year follow‐up, elimination of individuals with hsCRP >10 mg/L, competing‐risk analyses accounting for death, and further adjustment for detailed lipid‐lowering therapy categories. Conclusions Among patients with type 2 diabetes receiving lipid‐lowering therapy for primary prevention of PAD, elevated RC and systemic inflammation are independently and jointly associated with future PAD risk. These findings highlight substantial residual risk beyond managed low‐density lipoprotein cholesterol and support the need for further strategies targeting both remnant lipoproteins and inflammation in this high‐risk population.