OBJECTIVE Intensive glycemic control reduces the risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces the risk of lower-extremity complications is unknown. We examined whether former intensive versus conventional glycemic control among Diabetes Control and Complications Trial (DCCT) participants with T1D reduced the long-term risk of diabetic foot ulcers (DFUs) and lower-extremity amputations (LEAs) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS DCCT participants (n = 1,441) completed 6.5 years on average of intensive versus conventional diabetes treatment, after which 1,408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox proportional hazard regression models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA. RESULTS Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFUs (hazard ratio 0.77 [95% CI 0.60, 0.97]) and a similar magnitude but nonsignificant risk reduction for first-recorded DFUs (0.78 [0.59, 1.03]) and first LEAs (0.70 [0.36, 1.36]). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity, and cardiovascular autonomic neuropathy were associated with higher DFU risk; estimated glomerular filtration rate <60 mL/min/1.73 m², albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA_1c with higher risk of both outcomes (P < 0.05). CONCLUSIONS Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.

OBJECTIVE To describe incidence of foot ulceration and amputation-free survival associated with foot ulceration status in a national population-based cohort study of people with diabetes. RESEARCH DESIGN AND METHODS The study population included 233,459 people with diabetes who were alive in Scotland on 1 January 2012 identified from the national population-based register (national prevalence 4.9%). Characteristics of patients identified from linked hospital and mortality records during follow-up to the end of November 2017 were compared by outcome. Cox regression was used to assess the association between history of foot ulcer and amputation-free survival. RESULTS The population included 23,395 people with type 1 diabetes and 210,064 people with type 2 diabetes. In total there were 13,093 (5.6%) people who had a previous foot ulceration, 9,023 people who developed a first ulcer, 48,995 who died, and 2,866 who underwent minor or major amputation during follow-up. Overall incidence of first-time foot ulcers was 7.8 per 1,000 person-years (95% CI7.6–7.9) and 11.2 (11.0–11.4) for any ulcer. Risk factors for reduced amputation-free survival included social deprivation, mental illness, and being underweight in addition to conventional cardiovascular risk factors. Adjusted hazard ratios (95% CI) were 2.09 (1.89–2.31) for type 1 diabetes and 1.65 (1.60–1.70) for type 2 diabetes. CONCLUSIONS The overall incidence of foot ulceration in a population-based study of people with diabetes was 11.2 per 1,000 person-years. Foot ulceration is associated with lower amputation-free survival rate, a potential measure of effectiveness of care among people with diabetes. Mental illness and social deprivation are also highlighted as risk factors.

OBJECTIVE Diabetes is a leading cause of nontraumatic lower-extremity amputation (NLEA) in the U.S. After a period of decline, some national U.S. data have shown that diabetes-related NLEAs have recently increased, particularly among young and middle-aged adults. However, the trend for older adults is less clear. RESEARCH DESIGN AND METHODS To examine NLEA trends among older adults with diabetes (≥67 years), we used 100% Medicare claims for beneficiaries enrolled in Parts A and B, also known as fee for service (FFS). NLEA was defined as the highest-level amputation per patient per calendar year. Annual NLEA rates were estimated from 2000 to 2017 and stratified by age-group, sex, race/ethnicity, NLEA level (toe, foot, below-the-knee amputation [BKA], or above-the-knee amputation [AKA]), and state. All rates were age and sex standardized to the 2000 Medicare population. Trends over time were assessed using Joinpoint regression and annual percent change (APC) reported. RESULTS NLEA rates (per 1,000 people with diabetes) decreased by half from 8.5 in 2000 to 4.4 in 2009 (APC −7.9, P < 0.001). However, from 2009 onward, NLEA rates increased to 4.8 (APC 1.2, P < 0.01). Trends were similar across most age, sex, and race/ethnic groups, but absolute rates were highest in the oldest age-groups, Blacks, and men. By NLEA type, overall increases were driven by increases in rates of toe and foot NLEAs, while BKA and AKA continued to decline. The majority of U.S. states showed recent increases in NLEA, similar to national estimates. CONCLUSIONS This study of the U.S. Medicare FFS population shows that recent increases in diabetes-related NLEAs are also occurring in older populations but at a less severe rate than among younger adults (<65 years) in the general population. Preventive foot care has been shown to reduce rates of NLEA among adults with diabetes, and the findings of the study suggest that those with diabetes—across the age spectrum—could benefit from increased attention to this strategy.

OBJECTIVE Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk. RESEARCH DESIGN AND METHODS LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (Génétique de la Néphropathie Diabétique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3). RESULTS Among 478 participants (56% male, mean ± SD age 45 ± 12 years and diabetes duration 29 ± 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32–1.22] and for T3 vs. T1 0.41 [0.20–0.84]) but not with plasma 8-OHdG (1.16 [0.56–2.39] and 1.24 [0.61–2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during the 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08–0.67] and T3 vs. T1 0.29 [0.10–0.77]) and plasma 8-OHdG higher (2.20 [0.76–7.35] and 3.11 [1.07–10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA. CONCLUSIONS We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.

OBJECTIVE Nontraumatic lower-extremity amputation (NLEA) is a complication of end-stage renal disease (ESRD) and diabetes. Although recent data show that NLEA rates in the U.S. ESRD population are declining overall, trends in diabetes and diabetes subgroups remain unclear. RESEARCH DESIGN AND METHODS We estimated annual rates of NLEA hospitalizations during 2000–2015 among >2 million adults (≥18 years) with ESRD from the U.S. Renal Data System. Age, sex, and race-adjusted NLEA rates were stratified by diabetes status, age, sex, race, and level of amputation (toe, foot, below the knee, and above the knee). Time trends were assessed using Joinpoint regression with annual percent changes (APC) reported. RESULTS Among adults with diabetes, NLEA rates declined 43.8% between 2000 and 2013 (from 7.5 to 4.2 per 100 person-years; APC −4.9, P < 0.001) and then stabilized. Among adults without diabetes, rates of total NLEAs declined 25.5% between 2000 and 2013 (from 1.6 to 1.1; APC −3.0, P < 0.001) and then stabilized. These trends appear to be driven by a slowing or stagnation in declines of minor NLEAs (toe and foot) in more recent years, while major NLEAs (above the knee) continue to decline. CONCLUSIONS Despite an initial period of decline, this analysis documents a stall in progress in NLEA trends in recent years in a high-risk population with both ESRD and diabetes. Increased attention to preventive foot care in the ESRD population should be considered, particularly for those with diabetes.

OBJECTIVE To examine changes in diabetes-related preventable hospitalization costs and to determine the contribution of each underlying factor to these changes. RESEARCH DESIGN AND METHODS We used data from the 2001–2014 U.S. National (Nationwide) Inpatient Sample (NIS) for adults (≥18 years old) to estimate the trends in hospitalization costs (2014 USD) in total and by condition (short-term complications, long-term complications, uncontrolled diabetes, and lower-extremity amputation). Using regression and growth models, we estimated the relative contribution of following underlying factors: total number of hospitalizations, rate of hospitalization, the number of people with diabetes, mean cost per admission, length of stay, and cost per day. RESULTS During 2001–2014, the estimated total cost of diabetes-related preventable hospitalizations increased annually by 1.6% (92.9 million USD; P < 0.001). Of this 1.6% increase, 75% (1.2%) was due to the increase in the number of hospitalizations, which is a result of a 3.8% increase in diabetes population and a 2.6% decrease in the hospitalization rate, and 25% (0.4%) was due to the increase in cost per admission, for a net result of a 1.6% increase in cost per day and a 1.3% decline in mean length of stay. By component, the cost of short-term complications, lower-extremity amputations, and long-term complications increased annually by 4.2, 1.9, and 1.5%, respectively, while the cost of uncontrolled diabetes declined annually by 2.6%. CONCLUSIONS The total cost of diabetes-related preventable hospitalizations had been increasing during 2001–2014, mainly resulting from increases in number of people with diabetes and cost per hospitalization day. The underlying factors identified in our study could lead to efforts that may lower future hospitalization costs.

OBJECTIVE To determine whether declining trends in lower-extremity amputations have continued into the current decade. RESEARCH DESIGN AND METHODS We calculated hospitalization rates for nontraumatic lower-extremity amputation (NLEA) for the years 2000–2015 using nationally representative, serial cross-sectional data from the Nationwide Inpatient Sample on NLEA procedures and from the National Health Interview Survey for estimates of the populations with and without diabetes. RESULTS Age-adjusted NLEA rates per 1,000 adults with diabetes decreased 43% between 2000 (5.38 [95% CI 4.93–5.84]) and 2009 (3.07 [95% CI 2.79–3.34]) (P < 0.001) and then rebounded by 50% between 2009 and 2015 (4.62 [95% CI 4.25–5.00]) (P < 0.001). In contrast, age-adjusted NLEA rates per 1,000 adults without diabetes decreased 22%, from 0.23 per 1,000 (95% CI 0.22–0.25) in 2000 to 0.18 per 1,000 (95% CI 0.17–0.18) in 2015 (P < 0.001). The increase in diabetes-related NLEA rates between 2009 and 2015 was driven by a 62% increase in the rate of minor amputations (from 2.03 [95% CI 1.83–2.22] to 3.29 [95% CI 3.01–3.57], P < 0.001) and a smaller, but also statistically significant, 29% increase in major NLEAs (from 1.04 [95% CI 0.94–1.13] to 1.34 [95% CI 1.22–1.45]). The increases in rates of total, major, and minor amputations were most pronounced in young (age 18–44 years) and middle-aged (age 45–64 years) adults and more pronounced in men than women. CONCLUSIONS After a two-decade decline in lower-extremity amputations, the U.S. may now be experiencing a reversal in the progress, particularly in young and middle-aged adults.

OBJECTIVE The goal of the study was to determine whether complications of diabetes well-known to be associated with death such as cardiovascular disease and renal failure fully explain the higher rate of death in those who have undergone a lower-extremity amputation (LEA). RESEARCH DESIGN AND METHODS This was a longitudinal cohort study of patients cared for in the Health Improvement Network. Our primary exposure was LEA and outcome was all-cause death. Our “risk factor variables” included a history of cardiovascular disease (a history of myocardial infarctions, cerebrovascular accident, and peripheral vascular disease/arterial insufficiency), Charlson index, and a history of chronic kidney disease. We estimated the effect of LEA on death using Cox proportional hazards models. RESULTS The hazard ratio (HR) for death after an LEA was 3.02 (95% CI 2.90, 3.14). The fully adjusted (all risk factor variables) LEA HR was diminished only by ∼22% to 2.37 (2.27, 2.48). Furthermore, LEA had an area under the receiver operating curve (AUC) of 0.51, which is poorly predictive, and the fully adjusted model had an AUC of 0.77, which is better but not strongly predictive. Sensitivity analysis revealed that it is unlikely that there exists an unmeasured confounder that can fully explain the association of LEA with death. CONCLUSIONS Individuals with diabetes and an LEA are more likely to die at any given point in time than those who have diabetes but no LEA. While some of this variation can be explained by known complications of diabetes, there remains a large amount of unexplained variation.

OBJECTIVE Infection commonly complicates diabetic foot ulcers and is associated with a poor outcome. In a cohort of individuals with an infected diabetic foot ulcer, we aimed to determine independent predictors of lower-extremity amputation and the predictive value for amputation of the International Working Group on the Diabetic Foot (IWGDF) classification system and to develop a risk score for predicting amputation. RESEARCH DESIGN AND METHODS We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries. RESULTS Among these patients, 159 (28%) underwent an amputation. Independent risk factors for amputation were as follows: periwound edema, foul smell, (non)purulent exudate, deep ulcer, positive probe-to-bone test, pretibial edema, fever, and elevated C-reactive protein. Increasing IWGDF severity of infection also independently predicted amputation. We developed a risk score for any amputation and for amputations excluding the lesser toes (including the variables sex, pain on palpation, periwound edema, ulcer size, ulcer depth, and peripheral arterial disease) that predicted amputation better than the IWGDF system (area under the ROC curves 0.80, 0.78, and 0.67, respectively). CONCLUSIONS For individuals with an infected diabetic foot ulcer, we identified independent predictors of amputation, validated the prognostic value of the IWGDF classification system, and developed a new risk score for amputation that can be readily used in daily clinical practice. Our risk score may have better prognostic accuracy than the IWGDF system, the only currently available system, but our findings need to be validated in other cohorts.