Catherine L. Martin

Effect Of Prior Intensive Insulin Treatment During The Diabetes Control And Complications Trial (DCCT) On Peripheral Neuropathy In Type 1 Diabetes During The Epidemiology Of Diabetes Interventions, And Complications (EDIC) Study

OBJECTIVE To evaluate the impact of former intensive versus conventional insulin treatment on neuropathy in Diabetes Control and Complications Trial (DCCT) intensive and conventional treatment subjects with type 1 diabetes 13–14 years after DCCT closeout, during which time the two groups had achieved similar A1C levels. RESEARCH DESIGN AND METHODS Clinical and nerve conduction studies (NCSs) performed during the DCCT were repeated during the Epidemiology of Diabetes Interventions and Complications (EDIC) study by examiners masked to treatment status on 603 former intensive and 583 former conventional treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving two or more nerves among the median, peroneal, and sural nerves. RESULTS The prevalence of neuropathy increased 13–14 years after DCCT closeout from 9 to 25% in former intensive and from 17 to 35% in former conventional treatment groups, but the difference between groups remained significant (P < 0.001), and the incidence of neuropathy remained lower among former intensive (22%) than former conventional (28%) treatment subjects (P = 0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (odds ratio 1.17 [95% CI 0.84–1.63]). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean A1C and measures of incident and prevalent neuropathy. CONCLUSIONS The benefits of former intensive insulin treatment persisted for 13–14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.

Effects of Prior Intensive Insulin Therapy on Cardiac Autonomic Nervous System Function in Type 1 Diabetes Mellitus The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC)

Background— The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes mellitus. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive and conventional therapy subjects 13 to 14 years after DCCT closeout. Methods and Results— DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjustment for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in the former intensive group versus the former conventional group (28.9% versus 35.2%; P=0.018). Adjusted R-R variation was significantly greater in the former DCCT intensive versus the former conventional group (29.9 versus 25.9; P<0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% (odds ratio, 0.69; 95% confidence interval, 0.51 to 0.93) and of incident abnormal R-R variation by 30% (odds ratio, 0.70; 95% confidence interval, 0.51 to 0.96) in EDIC year 13/14. Conclusions— Although CAN prevalence increased in both groups, the incidence was significantly lower in the former intensive group compared with the former conventional group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.

Neuropathy and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

OBJECTIVE To describe the development and progression of neuropathy and related findings among patients with type 1 diabetes who participated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS The main diabetic peripheral neuropathy (DPN) outcome was assessed using clinical symptoms, signs, and nerve conduction study results during DCCT and repeated in EDIC year 13/14. Cardiovascular autonomic neuropathy (CAN) was assessed by R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing during DCCT and in EDIC years 13/14 and 16/17. Additionally, symptoms reflecting neuropathic pain and autonomic function (including hypoglycemia awareness) were collected yearly in EDIC using standardized questionnaires; peripheral neuropathy was also assessed annually using the Michigan Neuropathy Screening Instrument. Assessments of genitourinary function were collected at EDIC year 10. RESULTS Intensive therapy during the DCCT significantly reduced the risk of DPN and CAN at DCCT closeout (64% and 45%, respectively, P < 0.01). The prevalence and incidence of DPN and CAN remained significantly lower in the DCCT intensive therapy group compared with the DCCT conventional therapy group through EDIC year 13/14. CONCLUSIONS The persistent effects of prior intensive therapy on neuropathy measures through 14 years of EDIC largely mirror those observed for other diabetes complications. DCCT/EDIC provides important information on the influence of glycemic control, and the clinical course of diabetic neuropathy, and, most important, on how to prevent neuropathy in type 1 diabetes.

Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications

Diabet. Med. 29, 937–944 (2012)

DCCT and EDIC Studies in Type 1 Diabetes: Lessons for Diabetic Neuropathy Regarding Metabolic Memory and Natural History

The DCCT/EDIC (Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications) provides a comprehensive characterization of the natural history of diabetic neuropathy in patients with type 1 diabetes and provides insight into the impact of intensive insulin therapy in disease progression. The lessons learned about the natural history of distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy and the impact of glycemic control on neuropathy are discussed in this review.

Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications).

OBJECTIVES The goal of these studies was to determine the association between cardiovascular autonomic neuropathy (CAN) and indices of left ventricle (LV) structure and function in patients with type 1 diabetes (T1DM) in the DCCT/EDIC (Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications) study. BACKGROUND The pathophysiology of LV dysfunction in T1DM remains unclear, especially when the LV ejection fraction (EF) is preserved. Whether CAN is associated with LV dysfunction is unclear. METHODS Indices of LV structure and function were obtained by cardiac magnetic resonance imaging (CMRI). CAN was assessed by cardiovascular reflex testing (R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing). Analyses were performed in 966 DCCT/EDIC participants with valid CMRI and CAN data (mean age 51 years, 52% men, mean diabetes duration 29 years, and mean glycosylated hemoglobin 7.9%). RESULTS Systolic function (EF, end-systolic and end-diastolic volumes, stroke volumes) was not different in 371 subjects with CAN compared with 595 subjects without CAN. In multiple-adjusted analyses, participants with either abnormal R-R variation or a composite of abnormal R-R variation, abnormal Valsalva ratio, and postural blood pressure changes had significantly higher LV mass, mass-to-volume-ratio, and cardiac output compared with those with normal tests (p < 0.0001 for all). After further adjustment for traditional cardiovascular risk factors, subjects with abnormal R-R variation had higher LV mass and cardiac output compared with those with a normal R-R variation (p < 0.05). CONCLUSIONS In this large cohort of patients with T1DM, CAN is associated with increased LV mass and concentric remodeling as assessed by CMRI independent of age, sex, and other factors. (Diabetes Control and Complications Trial [DCCT]; NCT00360815) (Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893).

Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-Up Cohort A pilot study

OBJECTIVE To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN. RESULTS The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05–5.02], P = 0.03). CONCLUSIONS DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.

Glucose control and diabetic neuropathy: lessons from recent large clinical trials.

Diabetic peripheral and autonomic neuropathies are common complications of diabetes with broad spectrums of clinical manifestations and high morbidity. Studies using various agents to target the pathways implicated in the development and progression of diabetic neuropathy were promising in animal models. In humans, however, randomized controlled studies have failed to show efficacy on objective measures of neuropathy. The complex anatomy of the peripheral and autonomic nervous systems, the multitude of pathogenic mechanisms involved, and the lack of uniformity of neuropathy measures have likely contributed to these failures. To date, tight glycemic control is the only strategy convincingly shown to prevent or delay the development of neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in some patients with type 2 diabetes. Lessons learned about the role of glycemic control on distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy are discussed in this review.

Vibration Perception Threshold as a Measure of Distal Symmetrical Peripheral Neuropathy in Type 1 Diabetes Results from the DCCT/EDIC study

OBJECTIVE To describe the sensitivity, specificity, positive predictive value, and negative predictive value of vibration perception threshold (VPT) testing in subjects with type 1 diabetes relative to gold standard assessments of peripheral neuropathy. RESEARCH DESIGN AND METHODS VPT was determined in 1,177 adults with type 1 diabetes 13–14 years after participating in a study of intensive (INT) versus conventional (CONV) diabetes treatment. Abnormal VPT was defined by values exceeding 2.5 SD above age-specific normal values. Signs and symptoms of peripheral neuropathy were assessed and electrodiagnostic studies were performed to establish definite clinical neuropathy, abnormal nerve conduction, and confirmed clinical neuropathy (the presence of both definite clinical neuropathy and abnormal nerve conduction). RESULTS Thirty-seven percent of subjects had definite clinical neuropathy, 61% had abnormal nerve conduction, and 30% had confirmed clinical neuropathy. Abnormal VPT was more common among former CONV than among INT subjects (64 vs. 57%, P < 0.05) and was associated with older age. VPT was a sensitive measure of confirmed clinical neuropathy (87%) and of definite clinical neuropathy (80%) and a specific measure of abnormal nerve conduction (62%). Higher VPT cut points improved test sensitivity and lower cut points improved specificity. Areas under the receiver operating characteristic curves ranged from 0.71–0.83 and were higher for older than for younger subjects and highest for those with confirmed clinical neuropathy. CONCLUSIONS VPT was a sensitive measure of peripheral neuropathy. Future researchers may choose to select VPT cut points for defining abnormality based on the population studied and clinical outcome of interest.

Vibration Perception Threshold as a Measure of Distal Symmetrical Peripheral Neuropathy in Type 1 Diabetes: Results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)

OBJECTIVE To describe the sensitivity, specificity, positive predictive value, and negative predictive value of vibration perception threshold (VPT) testing in subjects with type 1 diabetes relative to gold standard assessments of peripheral neuropathy. RESEARCH DESIGN AND METHODS VPT was determined in 1,177 adults with type 1 diabetes 13–14 years after participating in a study of intensive (INT) versus conventional (CONV) diabetes treatment. Abnormal VPT was defined by values exceeding 2.5 SD above age-specific normal values. Signs and symptoms of peripheral neuropathy were assessed and electrodiagnostic studies were performed to establish definite clinical neuropathy, abnormal nerve conduction, and confirmed clinical neuropathy (the presence of both definite clinical neuropathy and abnormal nerve conduction). RESULTS Thirty-seven percent of subjects had definite clinical neuropathy, 61% had abnormal nerve conduction, and 30% had confirmed clinical neuropathy. Abnormal VPT was more common among former CONV than among INT subjects (64 vs. 57%, P < 0.05) and was associated with older age. VPT was a sensitive measure of confirmed clinical neuropathy (87%) and of definite clinical neuropathy (80%) and a specific measure of abnormal nerve conduction (62%). Higher VPT cut points improved test sensitivity and lower cut points improved specificity. Areas under the receiver operating characteristic curves ranged from 0.71–0.83 and were higher for older than for younger subjects and highest for those with confirmed clinical neuropathy. CONCLUSIONS VPT was a sensitive measure of peripheral neuropathy. Future researchers may choose to select VPT cut points for defining abnormality based on the population studied and clinical outcome of interest.