The ACCORD HRQL study was designed to detect meaningful change from baseline in HRQL associated with glycemic control treatment arms. Specifically, the prespecified objectives were to test potential treatment benefits from intensive glycemic versus standard therapy in terms of less symptom distress, improved general health (physical and psychological wellbeing), and improved treatment satisfaction. The impact of the intervention on depression, based on data from the Patient Health Questionnaire (18), is reported here as a secondary outcome.

Of the 10,251 patients enrolled in the ACCORD trial, a randomly selected subsample of 2,053 was enrolled in the ACCORD HRQL substudy. Of these, N = 1,024 had been randomized to intensive glycemic control and N = 1,029 to standard control.

Four distinct measures, general health, treatment satisfaction, diabetes-related symptoms, and depression, were used to measure HRQL. Data were collected by self-report questionnaire administered at the ACCORD baseline, 12-, 36-, and 48-month visits. General health status was assessed using the 36-Item Short Form Health Survey, Version 2 (SF-36) (19), where aggregate physical health (PH) and mental health (MH) component scores were calculated. The component scores are weighted combinations of individual items and have a general population norm of 50 and a standard deviation of 10, with higher scores representing better health. The PH component refers to ratings of limitations in physical, social, and role activities; severe bodily pain; fatigue; and self-rated health. The MH component refers to psychological distress, social and role disability as a result of emotional problems, and self-rated health.

A 60-item version of the Diabetes Symptoms Distress Checklist (DSC) (7) was used to assess the presence and severity (impact on functional status) of diabetes-related symptoms. Participants report whether or not they had experienced the given symptom or feeling and rate symptom distress on a scale of 0–4 (0 = not at all, 1 = somewhat, 2 = moderately, 3 = very much, 4 = extremely).

Satisfaction with diabetes treatment was assessed using the eight-item World Health Organization Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ), an authorized version identical to the DTSQ status version widely used in diabetes clinical trials (20). The DTSQ includes an overall six-item measure of satisfaction with the diabetes regimen with scores ranging from 0 to 36, with higher scores indicating higher satisfaction. For a subset of participants (ACCORD vanguard phase), only five satisfaction items were measured; therefore we converted the DTSQ score to a range from 0 to 100. In addition to the six-item measure, there were also two standard questions assessing perceived frequency of hyperglycemia and hypoglycemia ranging from 0 to 6, with higher scores indicating more frequent perception of high or low blood glucose.

Depression was assessed using the 9-item depression measure from the Patient Health Questionnaire (PHQ-9). The PHQ-9 is the self-report version of the PRIME-MD, a well-validated psychiatric diagnostic interview for use in primary care settings (18). Scores range from 0–27, and the score is treated as a continuous variable.

All statistical analyses were conducted using SAS software Version 9 (SAS Institute, Cary, NC). Statistical significance was defined as P value <0.05. Descriptive analyses of baseline clinical and HRQL characteristics were used to assess the representativeness of the HRQL subsample in relation to the ACCORD study population and to illustrate successful randomization of the HRQL substudy participants. Baseline characteristics of the two study groups were compared using χ² tests, t tests, and Wilcoxon tests.

To examine the effects of glycemic control treatment arm before the end of the glycemia trial on study outcomes of general health, treatment satisfaction, diabetes-related symptoms, and depression, each outcome measure was considered in three separate sets of repeated-measures linear models. We used data up until 5 February 2008, when the ACCORD glycemia trial was stopped. Each set modeled the change in the HRQL measure, and each set included the following terms: glycemia intervention, secondary trial assignment, prior CVD at baseline, the baseline HRQL measure, time, and a time-by-glycemia interaction term. A first set, as specified in the protocol, included only these measures. The second set added age, race, and sex. The final set added the set of covariates listed above.

We report the overall test of the glycemia term across all visits. We visually examined the estimated change in HRQL measure across the three time points in plots. Because it is possible that intensive glucose control increases, decreases, or leaves unchanged patients’ HRQL, we used two-sided P values to determine statistical significance as is conventional in clinical trial reports. Our prespecified α-level was 0.05. Although no formal adjustments for multiple comparisons were made, given the number of tests performed we estimate the probability of finding at least one model with a P value less than 0.05 to be 70.5%.

The glycemia intervention of ACCORD study was stopped early on 5 February 2008 because of higher mortality in the intensive group (21). All patients were transitioned to the standard glycemia-regimen and continued in the ACCORD blood-pressure and lipid studies for their planned durations of at least 4 years of follow-up. To assess potential effects of the transition to standard therapy on HRQL outcomes, we conducted an additional set of analyses including the HRQL data collected after the end of the glycemia trial. Not all participants had post-transition HRQL measures, and those that did have measures were at the months 36 and 48 visits. We added a term to the model to indicate whether the measure was post-transition and added an interaction term for post-transition and glycemia arm.

Table 1 presents the characteristics of the 2,053 participants who were included in the ACCORD HRQL substudy. There were no statistically significant differences in any of the characteristics examined by study sample. Clinical status of the HRQL substudy group at baseline was a mean HbA_1c of 8.3 ± 1%; means for weight and BMI were 94 kg and 32 kg/m², respectively, and the average duration of diabetes was 10 years (vs. 9 years in those not in the HRQL study, P = 0.0536), with ∼37% already on an insulin treatment regimen at baseline. A comparison of Table 1 covariates on ACCORD treatment group status of intensive glycemia (goal HbA_1c <6%) versus standard therapy (goal HbA_1c 7.0–7.9%) found no statistically significant results (data not shown).

Among ACCORD HRQL study participants, the analytic sample included 1,956 (95%) who completed one or more instruments within the baseline HRQL assessments (974/1,024 for intensive glycemia, and 982/1,029 for standard therapy). Sample sizes available for repeated-measures analysis of the HRQL follow-up at 12, 36, and 48 months were N = 921, N = 549, and N = 208 for intensive treatment and N = 937, N = 583, and N = 208 for standard therapy.

Table 2 presents baseline HRQL scores by ACCORD glycemia treatment group status. At baseline, ACCORD HRQL study participants reported lower physical health (PH component score) than the general population norm of 50.0 (means = 38.0 and 37.4 per treatment group), whereas psychological wellbeing was similar to the general population norm of 50.0 reported by Ware et al. (19). HRQL study participants in the intensive treatment group had statistically significantly higher physical health component score mean (i.e., somewhat better HRQL) and lower (i.e., somewhat worse) MH component score mean than those assigned to standard therapy, although these differences were very small. The mean number of nonzero diabetes-related symptoms assessed on the Diabetes Symptoms Distress Checklist total symptoms reported in the intensive and standard glycemia treatment groups was 17.2 and 16.9, respectively, with a mean symptom distress rating of ∼1.5, or the midpoint in the scale between somewhat and moderately. For the purposes of this study, diabetes treatment satisfaction assessed with the DTSQ treatment satisfaction scale, transformed to a percentage scale (0 to 100), was 72.5 vs. 74.0 and for the single item frequency ratings was a mean of ∼1.3 for perceived hypoglycemia and 3.6 for perceived hyperglycemia.

Results for the general linear models for repeated measures for the HRQL study outcomes through the active glycemia intervention are presented in Table 3. The results from the prespecified analyses, adjusted only for trial assignment and stratification variables, did not vary substantially from the results from a fully adjusted model including a variety of baseline covariates. After controlling for baseline covariates, change in HRQL over the 48-month duration in-trial was statistically significant for the SF-36 PH component, and DTSQ treatment satisfaction scale. For physical health, the intensive glycemic control arm had a slight (0.5 point) reduction in mean PH component change score (i.e., lowered HRQL) relative to those in the standard treatment arm (−1.6 vs. −1.1; P = 0.0345). For treatment satisfaction, DTSQ scores were significantly higher (i.e., greater satisfaction) than baseline in both groups, with a larger improvement in satisfaction with the treatment regimen (2.4 points; P = 0.0004) in the intensive arm. DTSQ single-item ratings of satisfaction with high and low blood glucose showed that participants in the intensive arm reported perceived improved (less) frequency of high blood glucose (−1.7 unit reduction from baseline, P < 0.0001), but perceived frequency of hypoglycemia was increased (0.8 unit increase from baseline, P < 0.0001).

Results for all time points grouped as pretransition and post-transition to the ACCORD standard glycemia-regimen and all data collected (not shown) revealed similar treatment group outcomes as the in-trial period results shown in Table 3, but with a somewhat larger improvement in mean DTSQ treatment satisfaction means in the intensive treatment group (pretransition: −0.8 vs. −0.8; post-transition: −0.8 vs. −1.2 for standard vs. intensive treatment groups, respectively). The difference between groups in the SF-36 PH and MH components was not statistically significant (P = 0.1279 and P = 0.1414, respectively). Group and transition (prepost) interactions for the HRQL outcomes were also tested, and none of the P values for interaction terms reached statistical significance.