A total of 926 people were randomized (ABPM study), of whom 759 had a valid baseline ABPM profile. Of these, 668 had at least one valid post-randomization ABPM profile (545 at both 6 and 12 months, 88 at 6 months only, 35 at 12 months only), forming the modified ITT population. Baseline characteristics are given in Table .
Clinical characteristics of the population studied
Approximately half of the participants were male and all but one was Europid. Within stratum the randomized groups were well matched, but the background metformin stratum was younger, more overweight and had shorter duration of diabetes than the sulfonylurea stratum. The presence of microalbuminuria at baseline was low in all four treatment groups. Eighty-four percent of participants had hypertension at baseline, already diagnosed (73%) or identified by the baseline ABPM (11%). Antihypertensive medication was being taken at baseline by 449 (67%) participants (single agent 207 participants [31%], two drugs 159 [24%], three or more drugs 83 [12%]). The distribution of class of antihypertensive treatment and number of agents was very similar in all four treatment groups (Table ).
Blood pressure lowering medication at baseline and end of follow-up
After 12 months, 96% of the participants in the modified ITT population were continuing to take their allocated dual oral glucose-lowering therapy. More participants in the metformin+rosiglitazone and sulfonylurea+rosiglitazone groups ceased dual combination treatment (8% and 5%, respectively) than in non-rosiglitazone groups (< 1% for both), the majority by progression to triple therapy (6% and 4%, respectively).
Changes in antihypertensive medication at end of follow-up were similar in all groups (Table ). Antihypertensive medication was started in the background metformin stratum in 27 (8%) participants (rosiglitazone 13; sulfonylurea 14), additional drugs were taken by 55 (16%) (rosiglitazone 31; sulfonylurea 24), and an increased dose in 18 (5%) (rosiglitazone 9; sulfonylurea 9). The same matched intensification was observed in the background sulfonylurea stratum: 24 participants (7%) started treatment (rosiglitazone 15; metformin 9), 39 (12%) added a new drug (rosiglitazone 19; metformin 20), and 15 (5%) increased the dose (rosiglitazone 7; metformin 8).
The time-course for first introducing new/increased antihypertensive medication during follow-up was similar for rosiglitazone-treated patients and the respective control groups (Log rank test p-value both > 0.50). Kaplan-Meier estimates of the proportion who introduced new/increased antihypertensive medication by 12 months were 30.1% (95% CI 23.2–37.0) and 28.7% (95% CI 21.6–35.7) of the background metformin participants on rosiglitazone and sulfonylurea, respectively, and 26.4% (95% CI 19.3–33.5) and 21.5% (95% CI 14.8–28.2) of background sulfonylurea participants using rosiglitazone and metformin, respectively.
24-hour ambulatory blood pressure
The majority of participants had at least 85% of valid readings during the 24-hour ABPM assessment. For rosiglitazone added to background sulfonylurea, the reduction in 24-hour sBP was significantly greater at both 6 (-3.8 mmHg) and 12 (-3.8 mmHg) months than with metformin added to sulfonylurea (-1.2 and -1.3 mmHg) (6 months, p = 0.015; 12 months, p = 0.031) (Figure and Table ). Reductions in 24-hour dBP were also statistically significantly greater at both 6 and 12 months with rosiglitazone added to sulfonylurea (-3.1 and -3.7 mmHg) than with metformin added to sulfonylurea (-0.4 and -0.6 mmHg; both p < 0.001).
Model-adjusted mean difference in ABPM for rosiglitazone compared to sulfonylurea and to metformin in combination therapy.
Change from baseline in 24-h ambulatory BP and heart rate at 6 and 12 months
At 12 months, the reduction in 24-hour sBP was significantly greater (p = 0.016) for rosiglitazone added to metformin (-4.9 mmHg) than for sulfonylurea added to metformin (-2.2 mmHg) (Figure and Table ). Diastolic BP at 12 months was also reduced to a greater extent by rosiglitazone added to metformin (-3.8 mmHg) than by sulfonylurea added to metformin (-1.7 mmHg; p = 0.003). At 6 months, both for sBP and dBP, the changes from baseline and difference between the treatment groups were less pronounced (sBP, p = NS; dBP, p = 0.049).
Data analysis for the sub-population with hypertension at baseline (84% of the study population) gave very similar results to those of the whole population (data not shown).
No sizeable correlation was found at 12 months between change in 24-hour ABPM and change in HOMA%S in any of the rosiglitazone treatment groups (r= -0.03 to -0.20) (data not shown). In addition, no sizeable correlation was found at 12 months between change in 24-hour ABPM and body weight change (r= -0.14 to 0.16; data not shown).
Similar increases in body weight from baseline to 12 months were observed in both arms of the metformin stratum (rosiglitazone: +1.9 kg [95% CI 1.3–2.6]; sulfonylurea: +1.5 kg [95% CI 1.0–2.1]; difference: 0.4, p = NS). In the sulfonylurea stratum there was a significant increase in body weight with rosiglitazone compared to a slight decrease with metformin (rosiglitazone: +2.2 kg [95% CI 1.6–2.7]; metformin: -1.1 kg [95% CI -1.5 to -0.6]; difference: 3.3, p < 0.0001).
Diurnal blood pressure contrasts
In general, the day- and night-time analyses were consistent with the 24-hour findings, with all the BP reductions on rosiglitazone at 12 months numerically greater than for comparator metformin and sulfonylurea arms, and in the majority of these sub-analyses statistically significant (Table ).
Contrast between day- and night-time effects of rosiglitazone on ambulatory BP at 12 months
For each contrast, the confidence intervals of the day- and night-time differences overlap. However, the effects of rosiglitazone compared with metformin tended to be larger during the night than during the day (day-night difference: sBP, p = 0.018; dBP, p = 0.020), while the effects compared to sulfonylurea tended to be larger or no different during the day (sBP, p = 0.052; dBP, p = NS).
The day-night profiles at 6 months were similar to those observed at 12 months (data not shown).
Ambulatory heart rate
The greater reductions in BP in the rosiglitazone groups were not accompanied by a compensatory increase in ambulatory heart rate (Table ). Heart rate did increase in the group in which metformin was added to sulfonylurea, such that adjusted heart rate changes from baseline at 6 and 12 months were statistically significantly lower with rosiglitazone (Table ).