Influence of micro- and macro-vascular disease and Tumor Necrosis Factor Receptor 1 on the level of lower-extremity amputation in patients with type 2 diabetes

Background: Patients with type 2 diabetes (T2D) face a high amputation rate. We investigated the relationship between the level of amputation and the presence of micro or macro-vascular disease and related circulating biomarkers, Tumor Necrosis Factor Receptor 1 (TNFR1) and Angiopoietin like-2 protein (ANGPTL2). Methods: We have analyzed data from 1468 T2D participants in a single center prospective cohort (the SURDIAGENE cohort). Our outcome was the occurrence of lower limb amputation categorized in minor (below-ankle) or major (above ankle) amputation. Microvascular disease was defined as a history of albuminuria [microalbuminuria: uACR (urinary albumine-to-creatinine ratio) 30-299 mg/g or macroalbuminuria: uACR >= 300 mg/g] and/or severe diabetic retinopathy or macular edema. Macrovascular disease at baseline was divided into peripheral arterial disease (PAD): peripheral artery revascularization and/or major amputation and in non-peripheral macrovascular disease: coronary artery revascularization, myocardial infarction, carotid artery revascularization, stroke. We used a proportional hazard model considering survival without minor or major amputation. Results: During a median follow-up period of 7 (0.5) years, 79 patients (5.5%) underwent amputation including 29 minor and 50 major amputations. History of PAD (HR 4.37 95% CI [2.11-9.07]; p < 0.001), severe diabetic retinopathy (2.69 [1.31-5.57]; p = 0.0073), male gender (10.12 [2.41-42.56]; p = 0.0016) and serum ANGPTL2 concentrations (1.25 [1.08-1.45]; p = 0.0025) were associated with minor amputation outcome. History of PAD (6.91 [3.75-12.72]; p < 0.0001), systolic blood pressure (1.02 [1.00-1.03]; p = 0.004), male gender (3.81 [1.67-8.71]; p = 0.002), and serum TNFR1 concentrations (HR 13.68 [5.57-33.59]; p < 0.0001) were associated with major amputation outcome. Urinary albumin excretion was not significantly associated with the risk of minor and major amputation. Conclusions: This study suggests that the risk factors associated with the minor vs. major amputation including biomarkers such as TNFR1 should be considered differently in patients with T2D.