OBJECTIVE: To use continuous glucose monitoring (CGM) to characterize diurnal glucose patterns produced by a novel formulation of exenatide consisting of biodegradable polymeric microspheres that entrap exenatide and provide extended release enabling once-weekly administration. METHODS: We performed a subgroup analysis of patients with type 2 diabetes who participated in a multicenter trial (DURATION-1: Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus) comparing once-weekly with twice-daily formulations of exenatide. We are the only center to use CGM with ambulatory glucose profile (AGP) analysis to characterize glucose exposure, variability, and stability in participants assigned to exenatide once weekly. RESULTS: Seven of the 303 patients in the larger study population were included in the subgroup analysis. Mean age (57.6 +/- 7 years), weight (102 +/- 17 kg), body mass index (34 +/- 3 kg/m2), and duration of diabetes (5 +/- 2 years) were comparable to characteristics of the larger study population. At 30 weeks and 52 weeks, participants treated with exenatide once weekly had a mean reduction in hemoglobin A1c level of 1.3 +/- 0.3% and 1.0 +/- 0.3%, respectively (P<.05). CGM analysis revealed a significant (P<.01) decrease in diurnal glucose exposure for 4 participants during nocturnal and daytime periods. Excess glucose exposure (compared with reference values) decreased in 6 of 7 participants, as did glucose variability. Glucose stability improved in 5 participants. The percentage of glucose values less than 70 mg/dL initially increased during the first half of the study then decreased to baseline levels by study end. CONCLUSIONS: Individual glucose profiles revealed that changes in hemoglobin A1c did not consistently parallel alterations in glucose exposure, variability, and stability. AGPs provided a visual representation of improved glucose responses to exenatide once weekly.