The baseline characteristics of the 1,116 EDIC participants and 325 nonparticipants (without all three IMT measurements) were similar except for A1C at eligibility (9.0 ± 1.6% for participants and 9.4 ± 1.7% for nonparticipants, P < 0.0001). The clinical characteristics at EDIC year 6 were not significantly different between the original DCCT treatment groups, with the exception of albumin excretion rates (), reflecting the persistent benefit of intensive treatment during DCCT. At DCCT close out, mean A1C levels were lower in the intensive treatment group (7.3 ± 1.0% vs. 9.0 ± 1.7% for women, 7.4 ± 1.0% vs. 9.1 ± 1.3% for men, P < 0.0001). Annual A1C levels were minimally different (0.1–0.4 A1C %), albeit nominally significant, between treatment groups during the first 6 years of EDIC but not during years 7 to 12 (data not shown). However, the weighted average over DCCT and EDIC up to EDIC years 1, 6, and 12 each remained significantly different between treatment groups (). A nominally significant difference between treatment groups was noted in the year 6 IMT among men but not women; however, the group by gender interaction was not statistically significant (P = 0.13). Thus, further analyses were conducted for the men and women combined.
Clinical characteristics of 1,116 EDIC participants with common carotid IMT measurements at years 1, 6, and 12 according to sex and original treatment assignment
and show the least squares means of carotid IMT progression from EDIC year 1 to years 6 and 12 from longitudinal regression models for repeated measurements, adjusted for baseline factors. The progression of IMT from EDIC years 1 to 6 was significantly less in the intensive compared with the conventional treatment group (−0.019 mm, P < 0.0001), as was the change from year 1 to 12 (−0.014 mm, P = 0.048; , ). However, the difference between treatment groups in the change in IMT from year 6 to 12 was not significant (+0.005 mm, P = 0.379). Similar results were obtained after adjusting for the current sBP and LDL, but the difference between groups in the change of carotid IMT from years 1 to 12 was no longer nominally significant (P = 0.083).
Change in least squares means* of common IMT over EDIC years 1, 6, and 12 by treatment group
FIG. 1. Least squares means in common carotid artery IMT based on linear mixed model adjusted for age, sex, study cohort, IMT reader, image device, and mean baseline IMT value of 0.614 mm. A significant separation in mean IMT between treatment groups (intensive, (more ...)
In the conventional treatment group, the mean change from year 1 to 6 (0.036 mm) was nominally lower than from year 6 to 12 (0.051 mm), but the difference was not significant (0.015 ± 0.012 mm, P = 0.211). In the intensive treatment group, the change in IMT from years 1 to 6 was very minimal (0.016 mm), but the change from years 6 to 12 (0.057 mm) was significantly greater (0.040 ± 0.012 mm, P < 0.0006) and similar to the change in the conventional treatment group during the same time period.
describes in the treatment groups combined the association of the mean A1C over DCCT and during different periods of DCCT and EDIC, with the IMT progression adjusted for the same factors as in . The mean A1C in DCCT and through EDIC year 1 had similar significant effects on the progression of IMT from year 1 to 6, whereas the EDIC mean A1C over years 1 to 6, and the DCCT/EDIC mean through year 6 had lesser effects. Likewise, the DCCT mean A1C and that over each subsequent EDIC period had a significant effect on the change in IMT over year 1 to 12. The DCCT mean A1C had a lesser effect on the change in IMT from years 6 to 12 relative to its effects on the changes from years 1 to 6 or years 1 to 12, in keeping with the pattern of treatment group differences in . Further, the EDIC mean A1C from years 1 to 6 and for years 1 to 12 had a stronger effect than that of the DCCT mean A1C alone. Averaging the A1C over DCCT and EDIC periods did not increase the effect of the EDIC mean A1C alone on progression from years 6 to 12. These results indicate that mean A1C during DCCT and EDIC up to the year of each assessment has the strongest association with the rate of progression in IMT up to that year.
Association of mean A1C in combined treatment groups during DCCT and EDIC with change in common carotid IMT over EDIC years 1, 6, and 12*
Adjustment for the current levels of sBP and LDL over each period (mean over 1–6, 1–12, and 6–12 years) attenuated the association of the different DCCT and/or EDIC A1C measures with the change in IMT over each period, the associations with the EDIC mean A1C measures no longer being significant. However, the associations of the DCCT mean and the DCCT/EDIC combined mean A1C with the changes from years 1 to 6 and years 1 to 12 remained significant, whereas the associations with the change in IMT from years 6 to 12 were nonsignificant. In these models, sBP was significantly associated with IMT progression (P < 0.0001) not LDL.
When the effect of intensive versus conventional therapy in is also adjusted for the DCCT mean A1C, the F test of the treatment group effects on progression from years 1 to 6 and years 1 to 12 are reduced by 87 and 96%, respectively. Thus, virtually all of these long-term treatment group differences in IMT progression are explained by the differences in A1C during the DCCT.
In models adjusting for the same factors as in , the progression of IMT from years 1 to 6 was greater by 0.013 ± 0.006 mm (P = 0.031) among those with microalbuminuria at any time up to EDIC year 1 versus not, but the difference among those with versus without microalbuminuria up to year 6 was smaller (P = 0.07). Progression from years 1 to 6 was also greater by 0.021 ± 0.01 mm (P = 0.043) among those with albuminuria up to year 6 versus not, but not among those with albuminuria versus not up to year 1 (P = 0.08). IMT progression from years 6 to 12 was greater by 0.014 ± 0.007 mm (P = 0.044) among those with microalbuminuria up to year 6, and by 0.020 ± 0.006 mm (P = 0.002) with microalbuminuria up to year 12 versus not; and by 0.022 ± 0.011 mm (P = 0.034) among those with albuminuria up to year 12, but not up to year 6 (P = 0.06) versus not. However, none of these differences in IMT progression remained significant when also adjusted for the DCCT/EDIC weighted mean A1C.
The multivariable risk factor models of common carotid IMT progression from years 1 to 6 and from years 6 to 12 (), adjusted for treatment group, explained approximately 51 and 57% of the variation in CCA IMT, respectively. Lipids (LDL, HDL, total cholesterol) did not add significantly to the models (P > 0.10). Smoking and an interaction of sBP and sex had significant effects on the change in IMT within both periods. In both models, the male-female difference increased as sBP at the beginning of the period increased, the difference being 0 at 104 mmHg for IMT progression from 1 to 6 years, and 109 for IMT progression from 6 to 12 years. In both models, men with sBP >120 mmHg (approximately) had significantly higher IMT progression (P = 0.05).
Multivariate risk factor models* for progression of common IMT years 1 to 6 and 6 to 12
A BMI ≥30 kg/m2 (obesity) at year 1 was not associated with IMT progression from years 1 to 6, but BMI ≥30 kg/m2 at year 6 was significantly associated with greater IMT progression from years 6 to 12. Because BMI differed between treatment groups, especially among women (), the two effects may be confounded. However, these BMI effects were similar in additional models adjusted for treatment group, or that adjusted for the DCCT/EDIC mean A1C up to the beginning of each period. Conversely, after adjustment for the prevalence of obesity, the effect of the DCCT/EDIC mean A1C up to year 1 on IMT progression from years 1 to 6 was unchanged, but the effect of the mean A1C to year 6 on IMT progression from years 6 to 12 was no longer significant (P = 0.23).