OBJECTIVE: Diabetes is the leading cause of nontraumatic lower-extremity amputations (LEAs). Identification of patients with foot ulcers at risk for amputation remains clinically challenging. Plasma copeptin, a surrogate marker of vasopressin, is associated with the risk of cardiovascular and renal complications in diabetes. RESEARCH DESIGN AND METHODS: We assessed the association between baseline plasma copeptin and risk of LEA during follow-up in four cohorts of people with type 1 (GENESIS, n = 503, and GENEDIAB, n = 207) or type 2 diabetes (DIABHYCAR, n = 3,101, and SURDIAGENE, n = 1,452) with a median duration of follow-up between 5 and 10 years. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. RESULTS: In the pooled cohorts with type 1 diabetes (n = 710), the cumulative incidence of LEA during follow-up by increasing tertiles (tertile 1 [TER1], TER2, and TER3) of baseline plasma copeptin was 3.9% (TER1), 3.3% (TER2), and 10.0% (TER3) (P = 0.002). Cox regression analyses confirmed the association of copeptin with LEA: hazard ratio (HR) for 1 SD increment of log[copeptin] was 1.89 (95% CI 1.28-2.82), P = 0.002. In the pooled cohorts of type 2 diabetes (n = 4,553), the cumulative incidence of LEA was 1.1% (TER1), 2.9% (TER2), and 3.6% (TER3) (P < 0.0001). In Cox regression analyses, baseline plasma copeptin was significantly associated with LEA: HR for 1 SD increment of log[copeptin] was 1.42 (1.15-1.74), P = 0.001. Similar results were observed in the cohort with type 2 diabetes for lower-limb revascularization (HR 1.20 [95% CI 1.03-1.39], P = 0.02). CONCLUSIONS: Baseline plasma copeptin is associated with cumulative incidence of LEA in cohorts of people with both type 1 and type 2 diabetes and may help to identify patients at risk for LEA.< Réduire