OBJECTIVES: The study's purpose was to identify the antihyperglycemic affects of colesevelam-HCl (C-HCl) by characterizing the diurnal and postprandial glucose patterns in type 2 diabetic subjects treated concomitantly with metformin, sulfonylurea, or a combination of metformin/sulfonylurea. A secondary aim was to determine whether C-HCl significantly increased the risk of hypoglycemia. METHODS: A prospective, randomized, double-blind, placebo-controlled, crossover study employing continuous glucose monitoring (CGM) with ambulatory glucose profile (AGP) analysis was undertaken. Fifteen males and 6 females, age 60 +/- 8 years, treated with metformin (n = 8), sulfonylurea (n = 2), or combination (n = 11) participated. RESULTS: Treatment with C-HCl led to reductions in glycated hemoglobin (HbA1c) (7.5 +/- 0.3 to 7.0 +/- 0.4% P<.0001), LDL (90.9 +/- 18.6 to 68.9 +/- 15.2 mg/dL, P<.0007) and total cholesterol (169.2 +/- 24.4 to 147.8 +/- 21.5 mg/dL, P<.001). Significantly lower normalized diurnal (21 mg/dL/hour, P = .0006), nocturnal (19 mg/dL/hour, P = .0005), and daytime (22 mg/dL/hour, P = .0008) glucose exposure was detected immediately upon C-HCl administration. Additionally, there was a significant (P<.004) decline in postprandial glucose excursions (averaging 15% or -36 mg/dL/hour) pronounced at dinner following C-HCl administration. There was a nonsignificant increase in the incidence of hypoglycemia (0.4-1%), with no difference due to antihyperglycemic medications. CONCLUSIONS: AGP analysis of CGM visually and quantitatively showed immediate and midterm impacts of C-HCl on basal and postprandial glucose patterns. This suggests a multifactorial glucose-lowering mechanism for C-HCl affecting both meal-related and basal glucose levels.