Results of the Glucose-Lowering Effect of WelChol Study (GLOWS): A randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes

Objective: This study evaluated the glycosylated hemoglobin (HbAc)-lowering effect of colesevelarn hydrochloride, a bile acid sequestrant, in subjects with type 2 diabetes that was inadequately controlled by existing antihyperglycemic therapy. Methods: After a 4-week placebo run-in period, subjects with type 2 diabetes and an HbA(1c) value of 7.0% to 10.0% were randomized to receive colesevelam 3.75 g/d or matching placebo for 12 weeks. Subjects' previous oral antihyperglycemic medication (sulfonylurea and/or metformin) was continued throughout the study. Fasting blood samples were obtained at weeks -5, -1, 0, 1, 4, 8, and 12. The primary efficacy end point was the change in HbA(1c) from baseline to week 12. Secondary end points included changes in fructosamine levels, fasting plasma glucose levels, postprandial glucose level, and meal glucose response (le, difference between preprandial and postprandial levels), and percent changes in lipid parameters from baseline to week 12. Results: The 65 randomized subjects (31 colesevelam, 34 placebo) had a mean age of 56.2 years and a mean body mass index of 32.4 kg/m(2); 55.4% were male and 53.8% were white. The difference in least squares (LS) mean (SE) change in HbA(1c) between the colesevelam group and the placebo group was -0.5% (0.18) (P = 0.007). In subjects with a baseline HbA(1c) >= 8.0%, the difference in LS mean change in HbA(1c) was -1.0% (0.27) (P = 0.002). Relative to placebo, colesevelam treatment was associated with reductions in levels of fructosamine (-29.0 [10.9] mu mol/L; P = 0.011) and postprandial glucose (-31.5 [13.6] mg/dL; P = 0.026). The mean percent change in low-density lipoprotein cholesterol was -9.6% in the colesevelarn group, compared with 2.1% in the placebo group (treatment difference, -11.7% [4.2]; P = 0.007); the respective mean percent changes in total cholesterol were -4.0% and 3.4% (treatment difference, -7.3% [3.0]; P = 0.019). Colesevelarn also was associated with significant decreases in the percent change in apolipoprotein B (P = 0.003) and low-density lipoprotein particle concentration (P = 0.037). The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups, although treatment-related adverse events were more frequent in the colesevelarn group than in the placebo group (29.0% vs 8.8%, respectively). The most frequent TEAEs in the colesevelam group were gastrointestinal disorders (22.6%), primarily constipation (19.4%), compared with an 8.8% incidence of gastrointestinal disorders (0% constipation) in the placebo group. There were no significant changes in body weight or the occurrence of hypoglycernia between treatment groups. Conclusions: In these subjects with type 2 diabetes, 12 weeks of colesevelarn treatment were associated with significant reductions in HbAlc and in fructosamine and postprandial glucose levels compared with placebo. The 2 groups had a similar adverse-event profile, with the exception of an increased incidence of constipation in the colesevelarn group. These results suggest that colesevelarn may improve both lipid control and glycemic control in patients with type 2 diabetes receiving oral antihyperglycemic medications.