Incident diabetic foot ulcer is the most powerful independent risk factor of lower‐extremity amputation in the prospective Seattle Diabetic Foot Study

Aims: To prospectively quantify the independent effect of incident diabetic foot ulcer (DFU) on lower-extremity amputation (LEA) risk, alongside person- and limb-level risk factors, in a cohort of male U.S. veterans with diabetes mellitus (DM).

Methods: A total of 1.458 male veterans with DM, contributing 2,893 ulcer-free lower limbs at baseline, were followed within the Seattle Diabetic Foot Study from 1990 to 2002 (mean follow-up 4.9 years). Baseline and repeated 12–18‑month evaluations collected demographic, clinical, biochemical, and detailed neurovascular limb-level measures (including ABI, lower‐limb transcutaneous oxygen pressure, neuropathy, Charcot deformity), and incident DFU and LEA were assessed through structured clinic follow-up and linkage to electronic records.

Results: Over follow-up, 227 incident DFUs (7.8% of limbs) and 72 LEAs (2.5% of limbs; 5.1/1000 limb-years) occurred, with 64 amputations (about 89%) preceded by an incident DFU. ​

In multivariable models with time-updated exposures, incident DFU was the strongest predictor of LEA (HR 10.44, 95% CI 6.01–18.15), while prior amputation, lower eGFR, higher systolic blood pressure, and severe PAD (ABI ≤0.5; HR 3.94, 95% CI 2.03–7.62) also independently increased the risk. Surprisingly, age ≥70 years was associated with lower LEA risk.

​Kaplan–Meier and hazard function plots showed a sharp rise in amputation hazard in the first ~500 days after DFU occurrence, with persistently elevated risk thereafter, whereas hazard remained relatively stable in limbs without DFU.

Conclusions: Incident DFU is the predominant independent driver of LEA in this veteran population, conferring roughly a tenfold increase in amputation risk beyond other limb and systemic risk factors.

​Preventing DFU occurrence and ensuring timely, effective ulcer healing are likely to result in the greatest reductions in diabetes-related amputations, particularly when integrated with aggressive management of peripheral arterial disease, renal impairment, and blood pressure.

Comments: The study provides a large prospective, limb-level quantification of the amputation risk conferred by incident DFU in limbs ulcer-free at baseline, rather than relying on historical or administrative DFU data. Use of time-updated covariates and flexible parametric survival modelling offers a description of how DFU onset impacts on amputation hazard over time. Comprehensive phenotyping at both people and limb level, including ABI, lower‐limb transcutaneous oxygen pressure, neuropathy and deformity, allows robust adjustment for key pathophysiological pathways.

​We have to acknowledge that the cohort consists almost exclusively of older male veterans with predominantly type 2 diabetes from a single centre, limiting generalizability of the results, especially to women, younger individuals and other clinical-social settings. Furhter, changes in diabetic foot care since the 1990 may attenuate some associations and could add a limit to direct applicability to contemporary practice.

However, in conclusion, this long prospective study higlisht how early detection and treatment of DFU is paramount to prevent LEA.

Luca D'Onofrio

Reference. Al-Busaidi IS, Seelig AD, Boyko EJ. Association of Incident Diabetic Foot Ulcer With Lower-Extremity Amputation Risk: The Prospective Seattle Diabetic Foot Study. Diabetes Metab Res Rev. 2025 Nov;41(8):e70102. doi: 10.1002/dmrr.70102. PMID: 41182892.

🔗 https://onlinelibrary.wiley.com/doi/10.1002/dmrr.70102