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

Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL. Clin Ther. 2007;29:74-83.

Diabetic complications can be delayed or even prevented if patients achieve tight glycemic control and meet targets for low-density lipoprotein cholesterol (LDL-C), but unfortunately most individuals with type 2 diabetes mellitus (T2DM) do not reach such objectives. Colesevelam hydrochloride, which is a bile acid sequestrant, is approved by the US FDA for use as a cholesterol-lowering agent, and previous studies have shown it can reduce blood glucose levels among subjects with T2DM. This pilot study was intended to evaluate the efficacy of colesevelam for glycemic control among patients with T2DM who were not achieving treatment goals while receiving oral antihyperglycemics.

This prospective, randomized, double-blind, placebo-controlled, parallel-group trial entitled Glucose-Lowering Effect of WelChol Study (GLOWS) was conducted at 15 locations in the US. Eligible subjects were 30-70 yrs old, met the American Diabetes Association (ADA) diagnostic criteria for T2DM, had A1C values 7%-10% at screening, and had been only taking stable doses of a sulfonylurea (SU) and/or metformin (MET) for ~90 days. In addition, they had body mass index (BMI) < 40 kg/m², fasting serum triglyceride (TG) levels < 300 mg/dL, and fasting plasma glucose (FPG) levels < 300 mg/dL. Participants entered a 4-week run-in period, during which they maintained existing antihyperglycemic regimens while receiving placebo. At the end of initial stage, patients were re-evaluated for adherence with placebo and A1C values, which had to be within .5% of the level at screening. Subjects who were eligible were then randomized to colesevelam 3.75 g/day or placebo for 12 weeks, during which they continued preexisting antihyperglycemic treatment regimens. The primary endpoint of this study was change in A1C from baseline to Week 12, and secondary end points included changes in differences between pre- and postprandial glucose levels, as well as fructosamine and FPG levels, and percent changes in lipid parameters, including LDL-C, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TG, apolipoprotein (apo) A-I and B, and LDL particle concentration.

Among all patients screened (n = 234), 109 entered the placebo run-in period, following which 65 were eligible, 31 of whom were randomized to colesevelam and 34 to placebo. The groups had similar baseline characteristics, and the most common antihyperglycemic regimen among those randomized to colesevelam was a combination of SU and MET (54.8%) in contrast to SU monotherapy (50%) among the placebo group.

Compared with the placebo group, patients treated with colesevelam had a significant reduction in A1C at Week 12 (P = .007). Among subjects with A1C ≥ 8% at baseline, the between-group difference in LS mean change = -1% (P = .002), whereas those with A1C <8% at baseline had a -.2% decrease that was not significant. There were no significant differences in LS mean changes of A1C between groups taking an SU (-.6%), MET (-.6%), or those receiving a SU and MET combination (-.5%).

At Week 4, the difference in LS mean change in FPG levels between groups = -23.3 mg/dL and was significant (P = .016), and it remained so at Week 8 (-18.3 mg/dL, P = .011) but not Week 12 (-14 mg/dL). Decreases in fructosamine levels were significantly greater in the colesevelam group at Week 12 (-29 μmol/L, P = .011), as were reductions in postprandial glucose (-31.5 mg/dL, P = .026). Additional significant improvements were found among levels of LDL-C (P = .007), TC (P = .019), and apo B (P = .003), as well as LDL particle concentration (P = .037). However, between-group changes were not significant in other lipid parameters and meal glucose response at Week 12.

AEs occurred among 20 (64.5%) subjects in the colesevelam group, 9 (29%) of whom had events considered by investigators to be treatment related, and among the 22 (64.7%) patients in the placebo group with AEs, 3 (8.8%) had those related to treatment. The most frequent treatment-emergent AEs among the colesevelam group were gastrointestinal disorders among 9 subjects compared to 3 in the placebo group. Between the groups no clinically important differences occurred in the incidence of hyper- or hypoglycemia. There were also no significant changes in body weight in either group, or significant between-group differences at Week 12.

The results of this study demonstrated that colesevelam can significantly improve glycemic control among patients with T2DM, especially among patients with A1C levels ≥ 8%. Colesevelam also reduced LDL-C, fructosamine, postprandial glucose, TC, and apo B. There were also significant decreases in FPG levels among the colesevelam group at Weeks 4 and 8, although they approached baseline levels at Week 12. Therefore, the authors concluded that studies of longer durations that include larger groups of patients may be necessary to determine the long-term impact of colesevelam on FPG levels. Participants treated with colesevelam had similar AE profiles as those that received placebo. This trial provided evidence that colesevelam may be a well-tolerated, effective agent for improving control of glycemia and LDL-C among patients with T2DM. Additional studies designed to assess the tolerability and efficacy of colesevelam for use as an oral antihyperglycemic agent that are currently in progress will provide further information regarding its safety and efficacy.