• Jaime A Davidson, Stephen O McMorn, Brian R Waterhouse, and Alexander R Cobitz.
• Department of Medicine, University of Texas, Southwestern Medical School, Dallas, Texas 75248, USA. davidsonmd@sbcglobal.net
• Clin Ther. 2007 Sep 1;29(9):1900-14.

BackgroundType 2 diabetes mellitus is twice as prevalent in African Americans and Hispanic Americans as in non-Hispanic whites. However, the effectiveness and safety profile of rosiglitazone maleate used as combination therapy with sulfonylureas in the management of diabetes and its effect on cardiovascular disease (CVD) biomarkers/parameters have not been studied in these populations.ObjectiveThe purpose of this study was to determine the efficacy and tolerability of the addition of rosiglitazone to a regimen of glyburide once daily in African American and Hispanic American patients with type 2 diabetes previously inadequately controlled with sulfonylurea monotherapy.MethodsThis randomized, double-blind, placebo-controlled, parallel-group study was conducted at 38 centers in the United States. Eligible patients were aged < or =21 years, had type 2 diabetes, a fasting plasma glucose (FPG) level > or =140 mg/dL, and a glycosylated hemoglobin (HbA(1c)) value > or =7.5%, and had been treated with sulfonylurea monotherapy for at least 2 months before screening. Patients were assigned to receive treatment with glyburide 10 or 20 mg/d plus rosiglitazone 8 mg (GLY+RSG) or placebo (GLY+PBO) PO (tablets) QD for 24 weeks. The primary efficacy end point was the change from baseline in HbA(1c) after 24 weeks of treatment. Secondary end points included change in FPG; proportion of patients achieving HbA(1c) targets (<7.0% and <6.5%); and changes in biomarkers for CVD risk, including C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-I activity, fibrinogen, tissue plasminogen activator (tPA) antigen, von Willebrand factor (vWF), soluble vascular cell adhesion molecule (sVCAM), lipoprotein-associated phospholipase A 2 activity, and urinary albumin/creatinine ratio (UACR). Tolerability was assessed using physical examination, including vital-sign measurement, clinical laboratory tests, and adverse event (AE) reports collected at each study visit.ResultsA total of 245 patients (101 African American and 144 Hispanic American) were enrolled. Demographic characteristics were comparable between the GLY+RSG and GLY+PBO groups: mean (SD) age (52 [11.9] vs 53 [10.4] years), HbA(1c) (9.2% [1.3%] vs 9.4% [1.4%]), sex (men/women, 45.3%/54.7% vs 48.3%/51.7%), race (African American/Hispanic American, 43.6%/56.4% vs 37.9%/62.1%), and mean (SD) weight (86.3 [18.8] vs 88.3 [19.4] kg). In the overall study population, treatment with GLY+RSG was associated with a significantly greater mean (95% CI) reduction from baseline in HbA(1c) compared with GLY+PBO (between-group Delta, -1.4% [-1.7% to -1.1%]; P < 0.001). When assessed by ethnicity, HbA(1c) values were significantly reduced with GLY+RSG compared with GLY+PBO in African American patients (between-group Delta, -1.4%) and in Hispanic American patients (between-group Delta, -1.5%) (both, P < 0.001), as were FPG levels (between-group Deltas, -3.1 mmol/L [57 mg/dL] and -3.8 mmol/L [-69 mg/dL], respectively; both, P < 0.001). With GLY+RSG, 9151 (17.6%) African American patients and 17/66 (25.8%) Hispanic American patients achieved HbA(1c) <7%, compared with 2/44 (4.5%) and 1/72 (1.4%) patients, respectively, who achieved this goal with GLY+PBO. Homeostasis model assessment estimates of insulin sensitivity and beta-cell function were significantly improved with GLY+RSG compared with GIX+PBO (between-group Deltas, 29.3% and 78.4%, respectively; both, P < 0.001). With regard to CVD biomarkers, there were potentially deleterious changes compared with baseline in the GLY+PBO group for CRP (+29.4%; P = 0.042), PAI-1 activity (+27.0%; P = 0.006), fibrinogen (+15.7%; P = 0.007), and sVCAM (+7.0%; P = 0.035), whereas there were no significant increases in these factors in the GLY+RSG group. In the GLY+RSG group, there were significant improvements in tPA (-17.8%; P < 0.001), vWF (-11.3%; P = 0.019), and UACR (-17.2%; P = 0.028) over 24 weeks' treatment, whereas there were no significant changes in any of these factors in the GLY+PBO group. As a result, significant treatment effects were observed for CRP (-29.2%; P = 0.019), tPA (-18.4%; P < 0.001), vWF (-12.9%; P < 0.015), and UACR (-26.7%; P = 0.006) with GLY+RSG compared with GLY+PBO. The most frequently reported AEs with GLY+RSG were edema and weight increase (both 121121 [9.9%] patients) and with GLY+PBO were upper respiratory tract infection (18/124 [14.5%] patients). AEs were reported in 83/121 (68.6%) patients in the GLY+RSG group, of which 6/121 (5.0%) were assessed as severe, compared with 70/124 ( 56.5 % ) patients who received GLY+PBO, of which 31124 (2.4%) were assessed as severe.ConclusionAdd-on rosiglitazone administered for 24 weeks was effective and well tolerated in these African American and Hispanic American patients with type 2 diabetes previously inadequately controlled on sulfonylurea monotherapy.

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