The study cohort comprised 150 subjects, including 74 randomized to rosiglitazone and 76 to placebo, recruited between February 2005 and October 2006. The disposition of patients in the trial is shown in Figure . Evaluable baseline and end-of-study assessments of the primary outcome, VO2peak–FFM, were available for 108 subjects (72%), 54 in each group. Of those completing the final study assessment, 103 completed all 6 months of therapy, with five participants undergoing early final assessments due to oedema and/or HF (four rosiglitazone; one placebo) at a mean treatment duration of 61 days. Baseline characteristics are presented in Table . Individuals not completing the study were younger (51.1 vs. 56.3 years; P = 0.001); more commonly Hispanic (33.3 vs. 16.7%; P = 0.03); and were less commonly treated with beta-blockers (19.1 vs. 38.9%; P = 0.02) and ACE inhibitors/angiotensin II receptor blockers (47.6 vs. 64.8%; P = 0.05). Among the subjects completing the trial comprising the primary analysis population, baseline characteristics were well-matched between the groups. Those completing the study had a mean age of 56 years, and included 41% women, 44% black, and 17% Hispanic subjects. On average, body mass index (BMI) was 34.1 kg/m2, with a mean duration of T2DM >9 years including >40% treated with insulin. The prevalence of hypertension and hyperlipidaemia were each about 75%, 35% had prior CVD, and 17% were smokers.
Flow of patients through the trial (MRI, magnetic resonance imaging; CPX, cardiopulmonary exercise test).
Baseline demographic and clinical characteristics at the time of randomization for those not completing the study, and among participants completing the trial, by treatment group
Clinical and laboratory results
Table summarizes clinical and laboratory values at baseline and study end for the 108 subjects who completed the study, with no statistically significant differences at baseline between the groups. At study entry, HbA1c was 7.6% in both treatment groups, declining during the study in both groups to 7.2% in the placebo vs. 6.9% in the rosiglitazone-treated group (P = 0.06; Figure ).
Baseline and end-of-study clinical parameters and laboratory values for those participants completing the trial
Changes in mean haemoglobin A1c during the trial.
Cardiopulmonary testing results
The exercise test results are presented in Table and Figure . After 6 months of study therapy, no significant differences were observed in the primary endpoint of mean VO2peak–FFM between rosiglitazone and placebo (26.1 vs. 27.6 mL/kg-FFM/min; P = 0.26); similarly, absolute VO2 (mL/min) or VO2 indexed to total body weight (mL/kg/min) were not statistically different between the groups.
Results of cardiopulmonary exercise testing among participants who completed the trial
Mean peak oxygen consumption during maximal treadmill exercise (VO2peak) by treatment group at baseline and at study end (A) indexed to fat-free mass (primary endpoint); (B) indexed to total body weight; and (C) absolute measure without indexation.
Within groups, VO2 indexed to total body weight (mL/kg/min) significantly decreased in the rosiglitazone group, with the magnitude of decline of 1.1 mL/kg/min, or 6% relative decline (P = 0.003); there were no significant changes in any of the other VO2 parameters within either group. In sensitivity analyses using baseline-observations-carried-forward for those not completing the study (n = 20; 27%), similar to analyses of those completing the study, there was no significant difference between rosiglitazone and placebo groups at study end in the primary outcome measure of VO2peak scaled to fat-free mass (26.35 vs. 27.49 mL/kg-ffm/min; P = 0.26). However, within the rosiglitazone group, the decline from baseline to study end was statistically significant (26.95 vs. 26.35 mL/kg-ffm/min; P = 0.026), though representing a relative change of only 2%.
Cardiac magnetic resonance imaging results
Of the 102 participants volunteering to undergo cMRI, 75 (74%) had complete baseline and end-of-study data, with results presented in Table . No significant differences were observed between the groups in LV mass index (83.2 vs. 75.2 g/m2; P = 0.06), end-systolic volume (44.4 vs. 39.1 mL; P = 0.28), or ejection fraction (66.1 vs. 65.9%; P = 0.9). Rosiglitazone vs. placebo was associated with significantly higher end-diastolic volume (128.1 vs. 112.0 mL; P = 0.01), stroke volume (83.7 vs. 72.9 mL; P = 0.01), and a trend toward improved peak filling rate (79.4 vs. 60.5; P = 0.07). Within groups, no significant changes were observed from baseline to end-of-study in cMRI parameters in the placebo group, whereas rosiglitazone was associated with statistically significant increases in end-diastolic volume (117.9 vs. 128.1 mL; P = 0.001); stroke volume (74.9 vs. 83.7 mL; P = 0004); and ejection fraction (63.8 vs. 66.1%; P = 0.03).
Results from cardiac magnetic resonance imaging
Evidence of volume expansion in subjects treated with rosiglitazone
Within the rosiglitazone group, significant increases in weight, BNP, and LV end-diastolic volume, and a significant decrease in hematocrit occurred over time, with no significant changes in these parameters in the placebo group (Figure A–D). Likewise, new or worse peripheral oedema was more common with rosiglitazone vs. placebo (53.7 vs. 33.3%; P = 0.03; Table ).
Changes in selected parameters during the trial suggesting plasma volume expansion, including (A) weight; (B) hematocrit; (C) circulating brain natriuretic peptide; and (D) left ventricular end-diastolic volume.
Safety and tolerability
Premature study drug discontinuation occurred in 20 subjects in the rosiglitazone group and 22 in the placebo group, most commonly for reasons unrelated to study therapy, excepting three patients in the rosiglitazone group and one in the placebo group stopping due to new or worsening peripheral oedema, and one in the rosiglitazone group for incident HF. Among those completing the study, compliance with study drug prescription was high and similar between the groups (89.9%). Three patients treated with rosiglitazone developed incident HF, two of whom had complete end-of-study assessments; no patients treated with placebo developed HF. Two patients had acute coronary syndrome events, both in the placebo group.