Neuropathy and Related Findings in the DCCT/EDIC Study
Neuropathy and Related Findings in the DCCT/EDIC Study
The clinical burdens of diabetic neuropathic complications are well recognized and result in significant morbidity. Painful symptoms are frequently refractory to treatment, and loss of protective sensation heightens the risk for foot ulceration and lower-extremity amputations. While symptoms associated with painful DPN and advanced autonomic dysfunction are often particularly troublesome, the earliest manifestations of CAN are silent and easily overlooked in clinical practice. Yet, CAN is an independent predictor of mortality, possibly by promoting life-threatening arrhythmias and sudden death in response to a variety of insults including drug side effects, hypoglycemia, hypokalemia, hypotension, or ischemia.
DPN and CAN were uncommon at the start of the DCCT, partly due to the intentional exclusion of people with neuropathy sufficiently severe to require treatment, but were increasingly prevalent over the DCCT/EDIC follow-up. INT during the DCCT decreased the development and progression of confirmed DPN and CAN relative to CON. Remarkably, treatment group differences were still measurable through 14 years of EDIC follow-up despite similar levels of glycemic control during EDIC.
The durable impact of prior treatment, even after disappearance of prior glycemic separation, first observed for retinopathy and nephropathy, has been described as "metabolic memory". Confirmed DPN increased in both INT and CON participants by EDIC year 13/14, but the treatment group differences observed for confirmed DPN at that time were eliminated by adjusting for nerve conduction variables at the end of the DCCT. Viewed differently, among subjects who did not have neuropathy at DCCT completion, those in the CON group were shown to have greater degrees of subclinical neuropathy than subjects in the INT group. This subclinical neuropathy represented an asymptomatic neuropathy that had not yet produced clinical signs or sufficiently abnormal electrophysiology and could partially explain the findings of continued difference in the development of DPN in the INT and CON groups during EDIC. Whether an additional influence of early intensive glucose control might have been apparent earlier during EDIC is unknown, but a persistent metabolic effect was not required to explain the durable beneficial effects on confirmed DPN in EDIC.
In contrast, a long-term beneficial influence of early intensive glucose control, first observed for retinopathy and nephropathy, was observed for CAN in EDIC. Modeling that adjusted for R-R variation at DCCT closeout did not negate the INT-associated risk reduction for development of CAN. The risk reduction for CAN is consistent with the "metabolic memory" effect observed for retinopathy and nephropathy. This apparent discordance in the impact of prior DCCT treatment group effect on longer-term outcomes for DPN and CAN may reflect differences in susceptibility of small- and large-nerve fibers to glycemic exposure.
In general, findings from studies of diabetic neuropathies have to be interpreted with caution, given the broad range of diagnostic methods employed and lack of consistency in the criteria used to define neuropathy. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), DPN was assessed by tactile or temperature sensitivity; and they reported abnormalities in 19–25% and 11–19% of participants, respectively, after 10 years of follow-up. In the Pittsburgh Epidemiology of Diabetes Complications Study (EDC), the cumulative incidence of DPN over a period of 5.3 years was 29%. In the EURODIAB Prospective Complications Study, an observational study that included 1,172 subjects with type 1 diabetes from 31 centers across Europe, neuropathy was defined by the presence of neuropathic symptoms, absence of ankle or knee reflexes, and abnormal vibration perception threshold as assessed by biothesiometers. EURODIAB reported that after only 7.3 years of follow-up, neuropathy developed in 24% of subjects, considerably higher than the 9% overall incidence of confirmed DPN reported over 5 years of follow-up in DCCT, which arguably used more stringent criteria that included nerve conduction studies. Although the differences in study design do not allow for precise comparisons between the true incidence of neuropathy in the DCCT/EDIC and the EURODIAB cohorts, EURODIAB also reported that HbA1c was an important determinant of neuropathy incidence.
The DCCT/EDIC is the first large study to concurrently obtain high-quality, standardized cardiac MRI and CAN evaluations, allowing for additional analyses regarding clinical implications of CAN. Although these cross-sectional findings prevent analysis of any causal relationship between CAN and ventricular dysfunction, other studies have demonstrated a relationship between sympathetic activation and left ventricular hypertrophy.
Genitourinary problems associated with diabetes, with the likely exception of impotence, are frequently overlooked in clinical practice and are rarely considered in the context of diabetic neuropathies. The Uro-EDIC study affords an opportunity to define the extent of genitourinary complications of diabetes and to explore the relationships of these to well-defined micro- and macrovascular complications, including neuropathy. In cross-sectional analyses, both erectile dysfunction and lower urinary tract symptoms in men were associated with DPN, perhaps due to shared or overlapping mechanisms of neuronal damage. These cross-sectional findings of associations between male genitourinary complications and DPN must be interpreted cautiously. Uro-EDIC data are being collected longitudinally and this may, in the future, shed light on shared pathophysiologic mechanisms between genitourinary and neuropathic complications.
The EDIC study continues to evaluate risk factors for neuropathic complications in a large number of well-characterized patients with type 1 diabetes and continues to demonstrate the value of optimizing glucose control as early as possible in the course of the disease to ameliorate the long-term effects of hyperglycemia. The DCCT and EDIC confirm that glycemic control is a significant and robust predictor of neuropathy. However, they also show that for most patients with type 1 diabetes, current strategies for optimizing glucose control are insufficient to fully prevent or delay the development of neuropathic complications, as 25% of subjects in the former INT group and 35% of subjects in the former CON group had confirmed DPN by 14 years of EDIC follow-up.
The reproducible, standardized DPN and CAN testing protocols, the robust and consistent definitions of neuropathy outcomes, the large sample size, and, most important, the commitment of DCCT/EDIC participants have allowed the DCCT/EDIC to provide invaluable lessons on the clinical course and the means of ameliorating DPN and CAN in patients with type 1 diabetes.
Conclusions
The clinical burdens of diabetic neuropathic complications are well recognized and result in significant morbidity. Painful symptoms are frequently refractory to treatment, and loss of protective sensation heightens the risk for foot ulceration and lower-extremity amputations. While symptoms associated with painful DPN and advanced autonomic dysfunction are often particularly troublesome, the earliest manifestations of CAN are silent and easily overlooked in clinical practice. Yet, CAN is an independent predictor of mortality, possibly by promoting life-threatening arrhythmias and sudden death in response to a variety of insults including drug side effects, hypoglycemia, hypokalemia, hypotension, or ischemia.
DPN and CAN were uncommon at the start of the DCCT, partly due to the intentional exclusion of people with neuropathy sufficiently severe to require treatment, but were increasingly prevalent over the DCCT/EDIC follow-up. INT during the DCCT decreased the development and progression of confirmed DPN and CAN relative to CON. Remarkably, treatment group differences were still measurable through 14 years of EDIC follow-up despite similar levels of glycemic control during EDIC.
The durable impact of prior treatment, even after disappearance of prior glycemic separation, first observed for retinopathy and nephropathy, has been described as "metabolic memory". Confirmed DPN increased in both INT and CON participants by EDIC year 13/14, but the treatment group differences observed for confirmed DPN at that time were eliminated by adjusting for nerve conduction variables at the end of the DCCT. Viewed differently, among subjects who did not have neuropathy at DCCT completion, those in the CON group were shown to have greater degrees of subclinical neuropathy than subjects in the INT group. This subclinical neuropathy represented an asymptomatic neuropathy that had not yet produced clinical signs or sufficiently abnormal electrophysiology and could partially explain the findings of continued difference in the development of DPN in the INT and CON groups during EDIC. Whether an additional influence of early intensive glucose control might have been apparent earlier during EDIC is unknown, but a persistent metabolic effect was not required to explain the durable beneficial effects on confirmed DPN in EDIC.
In contrast, a long-term beneficial influence of early intensive glucose control, first observed for retinopathy and nephropathy, was observed for CAN in EDIC. Modeling that adjusted for R-R variation at DCCT closeout did not negate the INT-associated risk reduction for development of CAN. The risk reduction for CAN is consistent with the "metabolic memory" effect observed for retinopathy and nephropathy. This apparent discordance in the impact of prior DCCT treatment group effect on longer-term outcomes for DPN and CAN may reflect differences in susceptibility of small- and large-nerve fibers to glycemic exposure.
In general, findings from studies of diabetic neuropathies have to be interpreted with caution, given the broad range of diagnostic methods employed and lack of consistency in the criteria used to define neuropathy. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), DPN was assessed by tactile or temperature sensitivity; and they reported abnormalities in 19–25% and 11–19% of participants, respectively, after 10 years of follow-up. In the Pittsburgh Epidemiology of Diabetes Complications Study (EDC), the cumulative incidence of DPN over a period of 5.3 years was 29%. In the EURODIAB Prospective Complications Study, an observational study that included 1,172 subjects with type 1 diabetes from 31 centers across Europe, neuropathy was defined by the presence of neuropathic symptoms, absence of ankle or knee reflexes, and abnormal vibration perception threshold as assessed by biothesiometers. EURODIAB reported that after only 7.3 years of follow-up, neuropathy developed in 24% of subjects, considerably higher than the 9% overall incidence of confirmed DPN reported over 5 years of follow-up in DCCT, which arguably used more stringent criteria that included nerve conduction studies. Although the differences in study design do not allow for precise comparisons between the true incidence of neuropathy in the DCCT/EDIC and the EURODIAB cohorts, EURODIAB also reported that HbA1c was an important determinant of neuropathy incidence.
The DCCT/EDIC is the first large study to concurrently obtain high-quality, standardized cardiac MRI and CAN evaluations, allowing for additional analyses regarding clinical implications of CAN. Although these cross-sectional findings prevent analysis of any causal relationship between CAN and ventricular dysfunction, other studies have demonstrated a relationship between sympathetic activation and left ventricular hypertrophy.
Genitourinary problems associated with diabetes, with the likely exception of impotence, are frequently overlooked in clinical practice and are rarely considered in the context of diabetic neuropathies. The Uro-EDIC study affords an opportunity to define the extent of genitourinary complications of diabetes and to explore the relationships of these to well-defined micro- and macrovascular complications, including neuropathy. In cross-sectional analyses, both erectile dysfunction and lower urinary tract symptoms in men were associated with DPN, perhaps due to shared or overlapping mechanisms of neuronal damage. These cross-sectional findings of associations between male genitourinary complications and DPN must be interpreted cautiously. Uro-EDIC data are being collected longitudinally and this may, in the future, shed light on shared pathophysiologic mechanisms between genitourinary and neuropathic complications.
The EDIC study continues to evaluate risk factors for neuropathic complications in a large number of well-characterized patients with type 1 diabetes and continues to demonstrate the value of optimizing glucose control as early as possible in the course of the disease to ameliorate the long-term effects of hyperglycemia. The DCCT and EDIC confirm that glycemic control is a significant and robust predictor of neuropathy. However, they also show that for most patients with type 1 diabetes, current strategies for optimizing glucose control are insufficient to fully prevent or delay the development of neuropathic complications, as 25% of subjects in the former INT group and 35% of subjects in the former CON group had confirmed DPN by 14 years of EDIC follow-up.
The reproducible, standardized DPN and CAN testing protocols, the robust and consistent definitions of neuropathy outcomes, the large sample size, and, most important, the commitment of DCCT/EDIC participants have allowed the DCCT/EDIC to provide invaluable lessons on the clinical course and the means of ameliorating DPN and CAN in patients with type 1 diabetes.
