For the 301 participants with available baseline CAC scans, the mean duration of diabetes was 12.1 ± 8.0 years and mean age 61.0 ± 9.0 years, most subjects were male (95%) and non-Hispanic white (65%), and prevalence of hypertension (79%) and prior CVD (38%) was high. Clinical characteristics for the 301 RACED participants were generally similar to those for the other VADT participants (). The minimum CAC Agatston score was 0 (present in 16%), while 25th, 50th (median), and 75th percentiles for CAC were 23, 276, and 872, respectively. Clinical characteristics by treatment group are shown in . The intensive group had lower triglycerides and higher HDL cholesterol (P
< 0.05 for both) but had similar levels of other risk factors. As in the VADT (14
), A1C levels in intensive and standard groups in the RACED substudy were well separated after 1 year (P
< 0.01), and the difference averaged ~1.5% units throughout the study ().
Comparison of clinical characteristics for RACED participants and for VADT participants who did not participate in RACED
Comparison of clinical characteristics of RACED participants according to VADT treatment assignment
FIG. 1. Time course of A1C levels for intensive (INT) and standard (STD) treatment groups. Median levels of A1C are shown by study year (0 = baseline); the P value for the overall difference between groups is <0.01. Shown above the x-axis are the total (more ...)
In the RACED cohort, a total of 89 participants experienced primary events over a median follow-up duration of 5.2 years. These events included 30 coronary, carotid, or peripheral revascularizations, 19 episodes of congestive heart failure, 16 myocardial infarctions, 10 strokes, 9 CVD deaths, 3 ischemic amputations, and 2 cases of severe but inoperable coronary artery disease. RACED participants who suffered a CVD event during follow-up were older, more likely to be non-Hispanic white, and had a longer history of diabetes, a greater prevalence of prior CVD, and lower HDL cholesterol (all P
< 0.05). The median CAC was significantly higher in those who had an event (P
< 0.01). Other characteristics did not differ significantly between those who did or did not develop clinical events. In this cohort, the reduction in CVD observed in the intensive treatment group was not significant (unadjusted HR 0.72 [0.47 – 1.10]; P
= 0.13), and was comparable to that found for the entire VADT (14
To test whether baseline CAC modified the influence of intensive glucose management (as assigned within the VADT) on future CVD events, we considered models including interactions between treatment and calcium [parameterized as log(CAC + 1) or dichotomized at 100]. In models including log(CAC + 1) or calcium categories (0–100 and >100), treatment, and calcium-by-treatment interaction but no adjustment for other covariates, the P values for interaction were 0.01 and 0.05, respectively, indicating that effects of intensive versus standard glucose management were modified by baseline CAC. After adjustment for relevant covariates, P values for interaction terms in corresponding multivariable models were 0.03 and 0.07, respectively, providing further support for differential effects of treatment according to level of CAC. A bootstrap analysis (using 2,000 samples) was also performed and identified the treatment, baseline CAC, interaction of baseline CAC with treatment, and prior CVD history as the four most important predictors of CVD events, each occurring in >73% of the repeated samplings (data not shown).
Kaplan-Meier curves for time to first CVD primary event () by treatment group for each of the four categories of CAC illustrate the modification of treatment effect with changes in baseline CAC. In the lowest two categories of calcium (CAC 0–10 and 11–100), participants randomized to receive intensive treatment had a CVD risk that was substantially lower than those randomized to standard therapy (P = 0.03 for those with CAC 0–10 and P = 0.12 for those with CAC 11–100). In fact, with these two low-CAC groups combined, a very low proportion of those receiving intensive therapy developed events (only 1 of 52 participants during follow-up; median time to event 5.2 years and maximum >6 years). In comparison, with the same two groups combined, a much larger proportion (11 of 62 participants) in the standard arm had an event. This corresponded to event rates of 4 and 39 per 1,000 person-years for those receiving intensive and standard therapy, respectively. The event types by treatment group are shown in the supplemental table in the online appendix. A comparison of risk factors and CAC scores between intensive and standard treatment arms in the combined lower CAC categories revealed no significant differences (), and any potentially relevant differences in these variables were accounted for in subsequent multivariable models. Similar results were present when individuals without previous CVD were excluded. In contrast, Kaplan-Meier curves for participants in the two higher CAC categories (101–400 and >400) demonstrated similar levels of CVD risk in both treatment groups. This occurred despite the fact that at baseline, triglyceride levels were lower and HDL cholesterol levels higher in the intensive treatment group (). The distribution of CVD events (supplemental Table 1) was similar between treatment groups in the higher two CAC categories.
FIG. 2. Kaplan-Meier curves for time to primary macrovascular end point by clinical categories of CAC (0–10 [A], 11–100 [B], 101–400 [C], and >400[D]) in those randomized to the standard (Std) or intensive (Int) therapy arm. Differences (more ...)
Comparison of clinical characteristics for RACED participants with lower (≤100) or higher (>100) CAC according to VADT treatment assignment
graphically displays HRs and CIs for the effect of intensive treatment for multivariable models fitted separately for subgroups with higher (>100) and lower (≤100) CAC. For the subgroup with higher CAC, the multivariable HR for the effect of treatment was 0.74 (95% CI 0.46–1.18; P = 0.21), while for those with lower CAC, the multivariable HR for treatment was 0.08 (0.008–0.77; P = 0.03). The magnitude of benefit of treatment across the range of CAC scores was further examined by estimating HRs for treatment from a multivariable model including age, ethnicity, diabetes duration, history of hypertension, history of smoking, prior CVD history, total and HDL cholesterol, and A1C as covariates and, additionally, log(CAC + 1), treatment, and calcium-by-treatment interaction. This analysis with CAC parameterized on the log scale was performed with data for all participants. This approach revealed that the benefit of intensive treatment diminished in a progressive manner across selected CAC scores of 0, 10, and 100, with HRs of 0.07 (0.01–0.55; P = 0.01), 0.16 (0.04–0.61; P < 0.01), and 0.34 (0.16–0.73; P < 0.01), and was completely absent at very high CAC scores (e.g., an HR of 0.75 [95% CI 0.47–1.19; P = 0.22] for a CAC score of 1,000). Additional sensitivity analyses, using CAC coded as tertiles (0–57, 58–641, and >641) or as three clinical categories (0–100, 101–400, and >400), yielded consistent results and demonstrated that the benefit of intensive glycemic control for CVD outcomes was apparent only for individuals in the lowest CAC category.
FIG. 3. HRs (95% CI) for effect of treatment (intensive vs. standard) in multivariable-adjusted models. Boxes represent HRs, and lines indicate 95% CI. P values indicate the significance of treatment effect in the indicated models. The treatment effect was estimated (more ...)