Neuropathy and Related Findings in the DCCT/EDIC Study
Neuropathy and Related Findings in the DCCT/EDIC Study
During DCCT, the prevalence of confirmed DPN increased slightly among INT group participants (from 7 to 9%), but substantially in CON subjects (from 5 to 17%, P < 0.001) ( Table 1 ). Significant treatment group differences were observed for all measures of incident DPN at the end of the DCCT. Adjusting for the presence of confirmed DPN at baseline, the INT risk reduction for incident neuropathy during the DCCT was 64% (95% CI 45–76).
The prevalence of all measures of DPN increased during EDIC, and treatment group differences continued to be significant ( Table 1 ). In EDIC, a 30% reduction in the risk of incident confirmed DPN was observed with prior INT (odds ratio [OR] 0.70 [95% CI 0.52– 0.93]) ( Table 2 ). Similar magnitude reductions were documented for several nerve conduction study measures.
One explanation for the finding of a persistent benefit of INT for confirmed DPN at EDIC year 13/14 could be the presence of different levels of subclinical neuropathy in the INT and CON groups at DCCT closeout, as any significant group difference in the nerve conduction results could influence the subsequent development of confirmed DPN during EDIC. This possibility was addressed using analytic models of incident neuropathy that adjusted for nerve conduction study results at DCCT closeout. These additional models negated the treatment group differences in development of neuropathy observed during EDIC. Specifically, after correction for difference in nerve conduction study results at DCCT closeout, no significant risk reduction was associated with former INT at EDIC years 13/14 (OR 1.17 [95% CI 0.84 –1.63]).
Logistic regression models were used to evaluate the effect of glycemic control on prevalent and incident DPN in EDIC. The odds of clinically evident DPN, abnormal nerve conduction studies, and confirmed DPN in EDIC (prevalence) each increased per unit (%) increase in DCCT mean HbA1c and EDIC mean HbA1c. The incidence of any of the three DPN outcomes during EDIC was increased with each unit increase in mean EDIC HbA1c. The DCCT mean HbA1c was associated only with increased odds for incident confirmed DPN in EDIC ( Table 3 ).
Vibration perception threshold was abnormally high at the great toe in 57% of former INT subjects versus 64% of former CON subjects (P < 0.05). The vibration perception threshold was lower (indicating better sensitivity) among former INT subjects (3.53 vibration units vs. 4.03 vibration units, P < 0.01).
The prevalence of DPN as measured by MNSI at the first year of EDIC was 1.8% versus 4.7% in INT and CON, respectively (P < 0.0001) by MNSI questionnaire and 17.8% versus 28.0% (P < 0.0001) by MNSI examination. Significant treatment group effects using MNSI criteria for DPN persisted through at least EDIC year 8. A 1% lower cumulative mean HbA1c (e.g., 8% [64 mmol/mol] to 7% [53 mmol/mol]) reduced the odds of DPN by 38% and by 27% for the questionnaire and examination, respectively. At year 14 of EDIC, the overall prevalence of DPN using the MNSI examination was 33%, closely mirroring the overall prevalence of concurrently measured confirmed DPN (30%).
Use of medication for neuropathic pain was reported by 7% of former INT participants and 6% of former CON participants at EDIC year 13/14. The difference was not statistically significant.
The prevalence of CAN was very low at the start of the DCCT (4% INT vs. 5% CON, P = NS). By DCCT end, the prevalence remained stable in INT, and had almost doubled in CON participants (5% vs. 9%, P = 0.0017) ( Table 1 ). The incidence of CAN was reduced by 45% with intensive treatment during the course of the DCCT.
The prevalence of CAN at EDIC year 13/14 was 29% INT vs. 35% CON, P = 0.018). Group differences were primarily driven by differences in R-R variation. The continuous R-R variation remained significantly higher in the INT group compared with the CON group, even after adjusting for important covariates including age, sex, and duration in DCCT (adjusted means 29.9 vs. 25.6, P < 0.001).
During EDIC, there was a 31% reduction in the risk for incident CAN in INT subjects who were free of CAN at DCCT closeout, with significant risk reductions remaining after adjustments that included age, R-R variation at DCCT closeout, medication use, and several other covariates ( Table 4 ). Virtually all of the treatment group difference in the incidence of CAN could be explained by the treatment group differences in mean HbA1c levels over time.
Comprehensive cardiovascular disease evaluations carried out during EDIC allowed for additional analyses to understand further the clinical implications of CAN. Associations between CAN and cardiac structure and function were analyzed in 966 EDIC participants with concomitant cardiac MRI and CAN measurements at EDIC year 16. Although parameters of left ventricle systolic function, including the ejection fraction, did not differ among EDIC participants with and without CAN, those participants with CAN had higher left ventricular mass and mass-to-volume ratios compared with participants without CAN (P < 0.0001 for each), changes consistent with left ventricular concentric remodeling that were independent of age, sex, and other traditional cardiovascular risk factors.
A small number of participants from both former treatment groups reported autonomic symptoms. Decreased adrenergic awareness of hypoglycemia (20% INT vs. 25% CON, P = NS) excessive postprandial epigastric fullness (8% INT vs. 8% CON, P = NS), and male impotence were among the most commonly reported symptoms at EDIC year 13/14.
Erectile dysfunction was ascertained in 591 men during EDIC year 10, as part of the Uro-EDIC. Erectile dysfunction was present in 23% of these men. No DCCT treatment group differences were observed for reported erectile dysfunction among men with diabetes duration of 1–5 years and who had no evidence of microvascular complications at DCCT entry (DCCT primary prevention cohort 17% INT vs. 20.3% CON, P = 0.49). Significant treatment group difference were observed among men with up to 15 years diabetes duration and retinopathy at DCCT entry (DCCT secondary intervention cohort 12.8% INT vs. 30.8% CON, P = 0.001). Age, DPN, and mean DCCT-EDIC HbA1c were significant risk factors associated with the presence of erectile dysfunction. Moderate to severe lower urinary tract symptoms were reported by 20% of men participating in Uro-EDIC and were associated with age and presence of peripheral neuropathy, but not with DCCT treatment group assignment. Of 550 women participating in Uro-EDIC, urinary incontinence was reported by 65%; 17% reported weekly or more frequent incontinence. There was no observed relationship with incontinence and DCCT treatment group assignment or presence of peripheral neuropathy.
Results
DPN
During DCCT, the prevalence of confirmed DPN increased slightly among INT group participants (from 7 to 9%), but substantially in CON subjects (from 5 to 17%, P < 0.001) ( Table 1 ). Significant treatment group differences were observed for all measures of incident DPN at the end of the DCCT. Adjusting for the presence of confirmed DPN at baseline, the INT risk reduction for incident neuropathy during the DCCT was 64% (95% CI 45–76).
The prevalence of all measures of DPN increased during EDIC, and treatment group differences continued to be significant ( Table 1 ). In EDIC, a 30% reduction in the risk of incident confirmed DPN was observed with prior INT (odds ratio [OR] 0.70 [95% CI 0.52– 0.93]) ( Table 2 ). Similar magnitude reductions were documented for several nerve conduction study measures.
One explanation for the finding of a persistent benefit of INT for confirmed DPN at EDIC year 13/14 could be the presence of different levels of subclinical neuropathy in the INT and CON groups at DCCT closeout, as any significant group difference in the nerve conduction results could influence the subsequent development of confirmed DPN during EDIC. This possibility was addressed using analytic models of incident neuropathy that adjusted for nerve conduction study results at DCCT closeout. These additional models negated the treatment group differences in development of neuropathy observed during EDIC. Specifically, after correction for difference in nerve conduction study results at DCCT closeout, no significant risk reduction was associated with former INT at EDIC years 13/14 (OR 1.17 [95% CI 0.84 –1.63]).
Logistic regression models were used to evaluate the effect of glycemic control on prevalent and incident DPN in EDIC. The odds of clinically evident DPN, abnormal nerve conduction studies, and confirmed DPN in EDIC (prevalence) each increased per unit (%) increase in DCCT mean HbA1c and EDIC mean HbA1c. The incidence of any of the three DPN outcomes during EDIC was increased with each unit increase in mean EDIC HbA1c. The DCCT mean HbA1c was associated only with increased odds for incident confirmed DPN in EDIC ( Table 3 ).
Vibration perception threshold was abnormally high at the great toe in 57% of former INT subjects versus 64% of former CON subjects (P < 0.05). The vibration perception threshold was lower (indicating better sensitivity) among former INT subjects (3.53 vibration units vs. 4.03 vibration units, P < 0.01).
The prevalence of DPN as measured by MNSI at the first year of EDIC was 1.8% versus 4.7% in INT and CON, respectively (P < 0.0001) by MNSI questionnaire and 17.8% versus 28.0% (P < 0.0001) by MNSI examination. Significant treatment group effects using MNSI criteria for DPN persisted through at least EDIC year 8. A 1% lower cumulative mean HbA1c (e.g., 8% [64 mmol/mol] to 7% [53 mmol/mol]) reduced the odds of DPN by 38% and by 27% for the questionnaire and examination, respectively. At year 14 of EDIC, the overall prevalence of DPN using the MNSI examination was 33%, closely mirroring the overall prevalence of concurrently measured confirmed DPN (30%).
Use of medication for neuropathic pain was reported by 7% of former INT participants and 6% of former CON participants at EDIC year 13/14. The difference was not statistically significant.
CAN
The prevalence of CAN was very low at the start of the DCCT (4% INT vs. 5% CON, P = NS). By DCCT end, the prevalence remained stable in INT, and had almost doubled in CON participants (5% vs. 9%, P = 0.0017) ( Table 1 ). The incidence of CAN was reduced by 45% with intensive treatment during the course of the DCCT.
The prevalence of CAN at EDIC year 13/14 was 29% INT vs. 35% CON, P = 0.018). Group differences were primarily driven by differences in R-R variation. The continuous R-R variation remained significantly higher in the INT group compared with the CON group, even after adjusting for important covariates including age, sex, and duration in DCCT (adjusted means 29.9 vs. 25.6, P < 0.001).
During EDIC, there was a 31% reduction in the risk for incident CAN in INT subjects who were free of CAN at DCCT closeout, with significant risk reductions remaining after adjustments that included age, R-R variation at DCCT closeout, medication use, and several other covariates ( Table 4 ). Virtually all of the treatment group difference in the incidence of CAN could be explained by the treatment group differences in mean HbA1c levels over time.
Comprehensive cardiovascular disease evaluations carried out during EDIC allowed for additional analyses to understand further the clinical implications of CAN. Associations between CAN and cardiac structure and function were analyzed in 966 EDIC participants with concomitant cardiac MRI and CAN measurements at EDIC year 16. Although parameters of left ventricle systolic function, including the ejection fraction, did not differ among EDIC participants with and without CAN, those participants with CAN had higher left ventricular mass and mass-to-volume ratios compared with participants without CAN (P < 0.0001 for each), changes consistent with left ventricular concentric remodeling that were independent of age, sex, and other traditional cardiovascular risk factors.
Other Autonomic and Genitourinary Outcomes
A small number of participants from both former treatment groups reported autonomic symptoms. Decreased adrenergic awareness of hypoglycemia (20% INT vs. 25% CON, P = NS) excessive postprandial epigastric fullness (8% INT vs. 8% CON, P = NS), and male impotence were among the most commonly reported symptoms at EDIC year 13/14.
Erectile dysfunction was ascertained in 591 men during EDIC year 10, as part of the Uro-EDIC. Erectile dysfunction was present in 23% of these men. No DCCT treatment group differences were observed for reported erectile dysfunction among men with diabetes duration of 1–5 years and who had no evidence of microvascular complications at DCCT entry (DCCT primary prevention cohort 17% INT vs. 20.3% CON, P = 0.49). Significant treatment group difference were observed among men with up to 15 years diabetes duration and retinopathy at DCCT entry (DCCT secondary intervention cohort 12.8% INT vs. 30.8% CON, P = 0.001). Age, DPN, and mean DCCT-EDIC HbA1c were significant risk factors associated with the presence of erectile dysfunction. Moderate to severe lower urinary tract symptoms were reported by 20% of men participating in Uro-EDIC and were associated with age and presence of peripheral neuropathy, but not with DCCT treatment group assignment. Of 550 women participating in Uro-EDIC, urinary incontinence was reported by 65%; 17% reported weekly or more frequent incontinence. There was no observed relationship with incontinence and DCCT treatment group assignment or presence of peripheral neuropathy.
