HbA1c and the Risk of Lower Limb Ulcers Among Diabetic Patients: An Observational and Genetics Study

<b>Aims:</b> A lower limb ulcer is a serious complication of diabetes. The association between glycated hemoglobin (HbA1c) and lower limb ulcers needs further clarification. We aimed to comprehensively evaluate the relationship between HbA1c and lower limb ulcer risk in diabetic patients through multivariable-adjusted observational analyses and Mendelian randomization (MR) approaches. <b>Methods:</b> This prospective cohort study included 23,434 individuals with prevalent diabetes in the UK Biobank. The Cox proportional hazard model was used to evaluate the association between HbA1c levels and lower limb ulcer risk. Furthermore, a one-sample MR analysis was conducted to explore the potential causal effect. <b>Results:</b>Over a follow-up period of 290,677 person-years (median length: 13.3 years), 1101 lower limb ulcers cases were documented. The multivariable-adjusted hazard ratios across categories of HbA1c of ≤ 42, 42-53, 53-64, 64-75, 75-86, and > 86 mmol/mol were 0.93 (0.76-1.15), 1.00, 1.24 (1.05-1.46), 1.98 (1.65-2.39), 2.68 (2.13-3.37), and 4.52 (3.62-5.65), respectively. The restrictive cubic spline model showed that lower limb ulcer risk increased steeply when HbA1c concentration exceeded 53 mmol/mol. One-sample linear and nonlinear MR analyses provided a positive but not significant association between genetically proxied HbA1c and lower limb ulcer risk among diabetic patients. <b>Conclusions:</b> High HbA1c levels increase the risk of lower limb ulcers in diabetic patients. MR analyses validated the positive but not significant association between genetically proxied HbA1c levels and lower limb ulcer risk. The results recommended an HbA1c goal of < 53 mmol/mol to decrease the incidence of diabetic ulcers.