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

Abstract

Abstract 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.

Keywords

• Amputation
• Microvascular disease
• Macrovascular disease
• Diabetic retinopathy
• Peripheral arterial disease
• Angiopoietin-like 2