At the closeout of the DCCT (ie, the EDIC baseline), the 1349 EDIC participants included herein had a mean age of 33 years and a mean duration of diabetes of 12 years (). At EDIC baseline, the DCCT treatment groups differed significantly in the median levels of AER (p<.001) and the prevalence of microalbuminuria (P<.001), but not albuminuria, reflecting the effects of DCCT therapy on these outcomes. The groups also differed significantly in levels of HbA1c (P<.001).
Participant Characteristics at EDIC Study Baseline
There were no differences in blood pressure or prevalence of hypertension at the end of the DCCT. The body mass index was significantly higher in the former intensive group at the end of the DCCT (P<.001). There were no differences in clearance of 125I-iothalamate, levels of serum creatinine, or standard creatinine clearance.
The difference in mean HbA1c level between the intensive- treatment and conventional-treatment groups maintained throughout the DCCT (7.2% vs 9.1%, respectively, for the EDIC participants reported herein; P<.001) began to narrow after DCCT closeout (). The mean values of HbA1c throughout the 8-year period of the EDIC study were 8.0% in the group that received intensive treatment during the DCCT and 8.2% in the group that received conventional treatment (P =.002 by Wilcoxon rank-sum test).
Distribution of HbA1c Concentration by Randomized Treatment Group at the End of the DCCT and in Each Year of the EDlC Study
Development of Microalbuminuria
Of 572 participants originally assigned to receive intensive treatment for diabetes and whose AERs were normal (<28 μg/min) at both the beginning andat the end of the DCCT, 39 (6.8%) of those at risk exhibited microalbuminuria at the EDIC Years 7 or 8 evaluation. Of 550 participants originally assigned to conventional treatment and with normoalbuminuria at both the beginning and at the end of the DCCT, 87 (15.8%) of those at risk had microalbuminuria at the year 7 or 8 evaluation. Intensive therapy carried out during the DCCT continued to reduce the odds of microalburminuria by 59% (95% confidence interval [CI], 39%-73%; P<.001) at the EDIC year 7 or 8 evaluation compared with 59% (95% CI, 36%-74%; P<.001) at the end of the DCCT, after adjusting for the corresponding baseline values. Microalbuminuria was consistently more prevalent in the former conventional-treatment group and the difference between the 2 treatment groups in the cumulative incidences of new cases of microalbuminuria after the end of DCCT also was significant (P<.001) (). Over the 8 years, the adjusted risk (hazard) reduction was 49% (95% CI, 32%-62%), likewise adjusted for EDIC baseline AER and odd vs even schedule of visits, compared with 39% (95% CI, 2 1%-52%; P<.001) during the 9 years of DCCT follow-up. This effect increased to a 57% risk reduction after adjustment for the presence of hypertension, level of body mass index, mean arterial pressure, and level of low-density lipoprotein cholesterol at DCCT closeout.
Prevalence and Cumulative Incidence of Microalbuminuria
Development of Clinical Albuminuria
Of 632 participants originally assigned to receive intensive therapy and who did not exhibit clinical alburminuria at the end of the DCCT, 9 (1.4%) of those at risk had clinical albuminuria at the EDIC year 7 or 8 evaluation compared with 59 of 630 participantsin the group receiving conventional treatment (9.4% of those at risk). After adjustment for the respective EDIC baseline values, intensive treatment in the DCCT continued to reduce the odds of clinical alburninuria: 84% (95% CI, 67%-92%; P<.001) at the year 7 or 8 evaluation in the EDlC study compared with 57% (95% CI, -1% to +81%; P=.05) at the end of the DCCT. As with microalbuminuria, the prevalence of alburminuria and the cumulative incidence of new cases after DCCT closeout between the 2 treatment groups differed significantly (), with an adjusted risk (hazard) reduction of 78% (95% CI, 58%-88%; P<.00l) compared with 54% (95% CI, 19%-74%; P<.001) during the 9 years of DCCT follow-up. This effect likewise increased to an 84% (95% CI, 68%-92%; P<.001) risk reduction after adjustment for other factors.
Prevalence and Incidence of Albuminuria
The continued salutary effects of DCCT intensive treatment on the development of albuminuria were present for different subsets, defined a priori. For example, in participants with normoalbuminuria at the end of the DCCT, after 8 years in the EDIC study there was a significant reduced odds of clinical albuminuria in the intensive-treatment group vs the conventional-treatment group (87% reduction; 95% CI, 65%-95%, P<.001). In participants with microalbuminuria at the end of the DCCT, after 8 years in the EDIC study there was also a significant reduced odds of clinical albuminuria in the intensive-treatment group (77% reduction; 95% CI, 25%-93%; P=.01).
Other Kidney Outcomes
At EDIC baseline there was no difference between treatment groups in the distribution of the GFR as assessed by 125I-iothalamate clearance, and very few participants had actual or estimated values less than 70 mL/min [1.2 mL/s] per 1.73 m2. There was no difference between groups in serum creatinine concentrations or standard creatinine clearance. During the EDIC study, slight but nominally significant differences in serum creatinine concentration emerged at years 7 or 8. By a generalized estimating equation analysis (due to skewness of the residuals) the mean serum creatinine concentration over EDIC years 1 through 8 was significantly lower in the former intensive-treatment group vs the conventional-treatment group (0.89 vs 0.92 mg/dL [78.7 vs 81.3 μmol/L], respectively; P<.001).
During the EDIC study, there were isolated, nominally significant differences between groups in the standard creatinine clearance values at years 2 through 8. By a generalized estimating equation analysis of the log clearance values, the geometric mean over the 8 years of the EDIC study approached significance (114.0 mL/min [l.9 mL/s] per 1.73 m2 with intensive treatment vs 112.7 mL/min [1.9 mL/s] per 1.73 m2 with conventional treatment, P=.07). After the 8 years of EDIC follow-up, the prevalence of a measured creatinine clearance less than 70 mL/min per 1.73 m2 in the intensive-treatment group was below 1%, compared with 4% in the conventional-treatment group (P<.001).
Twenty-seven patients doubled their serum creatinine concentration since DCCT baselie (), with 15 of these reaching a creatinine concentration of 2 mg/dL [176.8μm ol/L] or greater, with no significant difference between groups. In 16 patients this occurred during the average 6.5 years of DCCT follow-up. The number of those reaching a creatinine concentration of 2 mg/dL or greater was significantly lower in the intensive-treatment group vs the conventional-treatment group (5 vs 19, P=.004). Of these, 11 required dialysis or transplant (4 vs 7, P=.14) ().
Patients With Kidney Outcomes Through Year 8 in the EDIC Study*
While there was no difference between groups in levels of blood pressure during the DCCT, a difference between groups has emerged during the EDIC study. On average over the 8 years of follow-up, and adjusted for the level at the close of the DCCT, the mean level of systolic blood pressure was significantly lower in the participants in the former intensive-treatment group vs those in the conventional-treatment group (117.7 vs 119.0 mm Hg, P=.003), as was the mean arterial pressure (89.3 vs 90.0 mm Hg, P=.02). The slight difference in diastolic blood pressure was not significant (75.1 vs 75.6 mm Hg, P=.16). Likewise, although the prevalence of hypertension did not differ between treatment groups at the end of DCCT (11% in both groups, P=.81), more participants in the original conventional-treatment group developed hypertension over time, with the difference becoming significant during years 3 through 8 of the EDIC study (). By year 8 in the EDIC study, the prevalence of hypertension in the conventional-treatment group was 40.3% compared to 29.9% in the intensive-treatment group (P<.001) and hypertension was reduced by 40% with intensive vs conventional treatment (P.001). Among those participants who were normotensive at the end of the DCCT, former DCCT intensive therapy reduced the risk (hazard) of onset of hypertension by 32% (95% CI, 18%-44%, P<.00l) during the 8 years of EDEC follow-up, adjusted for DCCT and EDIC baseline covariates.
Prevalence of Hypertension at Each Year of the EDlC Study
These differences are not explained by differential use of antihypertensive medications. Beginning in year 1 of the EDIC study, 5.6% of the intensive-treatment group and 6.7% of the conventional- treatment group reported using angiotensin-converting enzyme inhibitors for any reason (eg, for hypertension, microalbuminuria, or both). By year 8 of the EDIC study, 21.6% of the intensive-treatment group and 29.0% of the conventional-treatment group reported using angiotensin-converting enzyme inhibitors.
Adjustment for EDIC Covariates
In additional proportional hazardsards models, the differences between DCCT treatment group in the risk of micro-albuminuria or clinical albuminuria remained highly significant after adjusting for the levels of median arterial pressure and incidence of hypertension during the EDIC study. These differences likewise remained significant after adjusting for the incidence of hyperlipidemia (low-density lipoprotein cholesterol level > 160 mg/dL [4.1 mmol/L] or use of antihyperlipidemic medication), body mass index, or GFR.
Among these covariates, the current prevalence of hypertension was highly significantly associated with increased risk of microalbuminuria and of albuminuria, but independently of the effect of DCCT intensive vs conventional therapy. The current prevalence of hypertension increased the risk of microalbuminuria by 68% (95% CI, 19%-138%; P=.004), yet DCCT group differences in hypertension explained only 2.9% of the effect of the DCCT treatment group on the risk of microalbuminuria. Hypertension increase the risk of albuminuria by 290% (95% C1, 126%-574%; P<.001) and explained 22.l% of the effect of DCCT treatment group. In each case the DCCT group effect remained significant at P<.001 after adjustment for hypertension during the EDIC study.
The DCCT group differences in risk of microalbuminuria and albuminuria also remained after adjustment for use of intensive vs conventional therapy during the EDIC study.
Effect of Glycemia
Proportional hazards regression models, adjusted for other factors, assessed the effect of the DCCT and EDIC combined mean HbA1c, level on the risk of new kidney events during the EDIC study among those at risk for such events during the study (ie, those event free during the DCCT). There was a 50.2% (95% CI, 42.2%-57.1%; P<.00l) reduction in the risk (incidence, hazard) of microalbuminuria per 10% reduction in the current combined mean HbA1c, level that explains 7.25% of the variation in risk. There was a 56.4% (95% CI, 43.4%-66.4% P<.001) reduction in the risk of clinical albuminuria per 10% reduction in the current combined mean HbA1c level that explains 3.31% of the variation in risk. The gradient is slightly steeper for clinical albuminuria than for microalbuminuria, but the strength of the effect is smaller (χ2 values of 42.2 vs 86.8, respectively), yielding a smaller proportion of variation explained. In part this may be due to the smaller number of events of clinical albuminuria vs microalbuminuria (73 vs 207, respectively).
In additional models that included both the DCCT and EDIC mean HbA1c levels separately, the EDIC HbA1c level over the 8 years of follow-up had a greater effect than the DCCT HbA1c level, each considered separately. For the analysis of microalbuminuria during the ED1C study, the DCCT mean HbA1c effect had a χ2 test value of 43.09 while the current EDIC mean HbA1c level had a value of 87.12 (P<.001 for both). For the analysis of albuminuria, the DCCT and EDIC HbA1c χ2 test values were 25.6 and 35.2, respectively. In each case, however, a model with separate DCCT and EDIC effects did not provide better fit than the model using the combined mean HbA1c level.
Since the DCCT mean HbA1c level continues to affect risk of onset of albuminuria during the EDIC study, and since the groups differed substantially with respect to DCCT HbA1c level but only slightly with respect to EDIC HbA1c level, it follows that the prolonged effect of DCCT intensive therapy is almost completely explained by the differences in the mean HbA1c level in the DCCT but not in the EDIC study. The χ2 test value for the effect of treatment group on risk of microalbuminuria was 21.45. Adjustment for the DCCT mean HbA1c level explains 91% of this group effect, while adjustment for the EDIC mean HbA1c level (in a separate model) explains 23%. Likewise, the group effect on risk of albuminuria was χ2= 20.98, of which 99% is explained by the mean DCCT HbA1c level and 16% by the EDIC level (separately). The fact that the ED1 C HbA1c level explains some of the group difference may be more a reflection of its correlation with the DCCT level than an independent effect.