AIMS: In the initial 26-week, double-blind, double-dummy assessment period of the DURATION-2 trial in patients with Type 2 diabetes on metformin, the once-weekly glucagon-like peptide 1 (GLP-1) receptor agonist exenatide once-weekly resulted in greater HbA(1c) improvement and weight reduction compared with maximum approved daily doses of sitagliptin or pioglitazone. This subsequent, 26-week, open-label, uncontrolled assessment period evaluated the safety and efficacy of (i) continued exenatide once-weekly treatment and (ii) switching from sitagliptin or pioglitazone to exenatide once-weekly. METHODS: Randomised oral medications were discontinued and all patients received exenatide once-weekly. Of the 364 patients [original baseline HbA(1c) 8.5 +/- 1.1% (70 mmol/mol), fasting plasma glucose 9.0 +/- 2.5 mmol/l, weight 88 +/- 20 kg) who continued into the open-label period, 319 patients (88%) completed 52 weeks. RESULTS: Evaluable patients who received only exenatide once-weekly demonstrated significant 52-week improvements (least square mean +/- se) in HbA(1c) (-1.6 +/- 0.1%), fasting plasma glucose (-1.8 +/- 0.3 mmol/l) and weight (-1.8 +/- 0.5 kg). Evaluable patients who switched from sitagliptin to exenatide once-weekly demonstrated significant incremental improvements in HbA(1c) (-0.3 +/- 0.1%), fasting plasma glucose (-0.7 +/- 0.2 mmol/l) and weight (-1.1 +/- 0.3 kg). Patients who switched from pioglitazone to exenatide once-weekly maintained HbA(1c) and fasting plasma glucose improvements (week 52: -1.6 +/- 0.1%, -1.7 +/- 0.3 mmol/l), with significant weight reduction (-3.0 +/- 0.3 kg). Exenatide once-weekly was generally well tolerated and adverse events were predominantly mild or moderate in intensity. Nausea was the most frequent adverse event in this assessment period (intent-to-treat: exenatide once-weekly-only 5%; sitagliptin-->exenatide once-weekly 11%; pioglitazone-->exenatide once-weekly 10%). No major hypoglycaemia was observed. CONCLUSIONS: Patients who switched to once-weekly exenatide from daily sitagliptin or pioglitazone had improved or sustained glycaemic control, with weight loss.