Risk of Foot Ulcer and Lower-Extremity Amputation Among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

Objective: Intensive glycemic control reduces risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces 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 (DFU) and lower extremity amputations (LEA) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study. <p>Research Design and Methods: DCCT participants [n=1441] completed 6.5 years on average of intensive vs conventional diabetes treatment, after which 1408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA. </p> <p>Results: Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFU (Hazard Ratio [HR] 0.77, 95% CI 0.60 to 0.97), and a similar magnitude but nonsignificant risk reduction for first recorded DFU (HR 0.78, 95% CI 0.59 to 1.03) and first LEA (HR 0.70, 95% CI 0.36 to 1.36). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity and cardiovascular autonomic neuropathy were associated with higher DFU risk; eGFR < 60 mL/min/1.73 m², albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA1c with higher risk of both outcomes (p<0.05).</p> <p>Conclusions: Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.</p>

Risk of Foot Ulcer and Lower-Extremity Amputation Among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

Objective: Intensive glycemic control reduces risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces 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 (DFU) and lower extremity amputations (LEA) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study. <p>Research Design and Methods: DCCT participants [n=1441] completed 6.5 years on average of intensive vs conventional diabetes treatment, after which 1408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA. </p> <p>Results: Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFU (Hazard Ratio [HR] 0.77, 95% CI 0.60 to 0.97), and a similar magnitude but nonsignificant risk reduction for first recorded DFU (HR 0.78, 95% CI 0.59 to 1.03) and first LEA (HR 0.70, 95% CI 0.36 to 1.36). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity and cardiovascular autonomic neuropathy were associated with higher DFU risk; eGFR < 60 mL/min/1.73 m², albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA1c with higher risk of both outcomes (p<0.05).</p> <p>Conclusions: Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.</p>

Risk of Foot Ulcer and Lower-Extremity Amputation Among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

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 &lt;60 mL/min/1.73 m2, albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA1c with higher risk of both outcomes (P &lt; 0.05). CONCLUSIONS Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.

Diabetic Peripheral Neuropathy and Urological Complications in Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study

Objective: <br>To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes. <br>ResearchDesignandMethods: <br>Measurements of DPN at EDIC years 1, 13/14 and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 yrs, diabetes duration 29.5 yrs) and 371 women (mean age 50.6 yrs and diabetes duration 29.8 yrs) enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. DPN was defined by symptoms, signs and abnormal electrophysiology, or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores. <br>Results: <br>Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men, and female sexual dysfunction (FSD), LUTS and urinary incontinence (UI) in 16% of women. When controlling for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides and statin medication use, men with confirmed DPN at EDIC year 13/14 had a higher odds of ED/LUTS at year 17 compared to men without DPN (OR=3.52 95% CI 1.69,7.31). Men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of ED and LUTS at year 17 than men without DPN at all time points. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared to those without FSD or LUTS/UI at EDIC year 17. <br>Conclusions: <br>In long-standing T1D, DPN is associated with the later development of urological complications in men. <b></b>

Diabetic Peripheral Neuropathy and Urological Complications in Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study

Objective: <br>To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes. <br>ResearchDesignandMethods: <br>Measurements of DPN at EDIC years 1, 13/14 and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 yrs, diabetes duration 29.5 yrs) and 371 women (mean age 50.6 yrs and diabetes duration 29.8 yrs) enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. DPN was defined by symptoms, signs and abnormal electrophysiology, or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores. <br>Results: <br>Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men, and female sexual dysfunction (FSD), LUTS and urinary incontinence (UI) in 16% of women. When controlling for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides and statin medication use, men with confirmed DPN at EDIC year 13/14 had a higher odds of ED/LUTS at year 17 compared to men without DPN (OR=3.52 95% CI 1.69,7.31). Men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of ED and LUTS at year 17 than men without DPN at all time points. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared to those without FSD or LUTS/UI at EDIC year 17. <br>Conclusions: <br>In long-standing T1D, DPN is associated with the later development of urological complications in men. <b></b>

Understanding Metabolic Memory: The Prolonged Influence of Glycemia During the Diabetes Control and Complications Trial (DCCT) on Future Risks of Complications During the Study of the Epidemiology of Diabetes Interventions and Complications (EDIC)

The Diabetes Control and Complications Trial (DCCT, 1983-1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 9.0%) markedly reduced the risks of retinopathy, nephropathy and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications study (EDIC, 1994 to date). <p>Early in EDIC, mean HbA1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. </p> <p>In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon, and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes.</p> <p>The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.</p>

Understanding Metabolic Memory: The Prolonged Influence of Glycemia During the Diabetes Control and Complications Trial (DCCT) on Future Risks of Complications During the Study of the Epidemiology of Diabetes Interventions and Complications (EDIC)

The Diabetes Control and Complications Trial (DCCT, 1983-1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 9.0%) markedly reduced the risks of retinopathy, nephropathy and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications study (EDIC, 1994 to date). <p>Early in EDIC, mean HbA1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. </p> <p>In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon, and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes.</p> <p>The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.</p>