We examined whether prior intensive glycemic control during the DCCT reduced the risk of diabetic foot ulcer (DFU) and lower extremity amputation (LEA) among participants with type 1 diabetes in the EDIC study. DFU and LEA occurrence were determined by physical examination during annual EDIC follow-up visits that began about one year following DCCT completion. We also assessed DFU and LEA risk by neurovascular measurements, diabetes characteristics, and clinical factors. Data were available from 23 years of EDIC follow-up. Recurrent DFU was defined if reported on a different limb in subsequent years or the same limb in non-consecutive years. Multivariable Cox models were used to estimate the association of intensive glycemic control and other time-updated risk factors with incident or total (incident + recurrent) DFU or incident LEA. Incident DFU was observed in 86 of the 699 former intensive and 109 of the 7former conventional treatment participants (HR 0.78, 95% CI 0.59 to 1.03). Total DFU numbered 117 in intensive (7.3/1000 person-years (p-y)) and 153 in conventional treatment participants (9.6/1000 p-y) for a significant risk reduction (HR 0.76, 95% CI 0.60 to 0.97, p=0.03). Incident LEA occurred in 15 intensive (1.0/1000 p-y) compared to 21 conventional treatment participants (1.4/1000 p-y, HR 0.70, 95% CI 0.36 to 1.36, p=0.30). Greater HbA1c, lower eGFR, albuminuria, confirmed clinical neuropathy, lower nerve conduction velocity, abnormal cardiovascular autonomic function, proliferative retinopathy, and macular edema were independently associated (p<0.05) with higher risk of incident DFU and LEA. Current smoking was associated with higher risk of LEA only. Ankle-brachial index measured continuously was not associated with risk of either outcome. We conclude that intensive glycemic control decreases the risk of DFU, the most important antecedent in the causal pathway to LEA.
E.J. Boyko: None. L. Zelnick: None. B. Braffett: None. R. Pop-Busui: Research Support; Self; AstraZeneca. C.C. Cowie: None. G.M. Lorenzi: Advisory Panel; Self; Intarcia Therapeutics, Inc.. R. Gubitosi-Klug: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott. I. de Boer: Research Support; Self; Medtronic, Abbott. Consultant; Self; Boehringer Ingelheim GmbH, Ironwood Pharmaceuticals, Inc..