We have observed marked variation in responses between and within patients to the incretin-mimetic exenatide. The aim of this study was to examine real life responses to exenatide (Byetta®) in indigenous patients with type 2 diabetes. Methods: An audit was undertaken on all indigenous patients who were prescribed exenatide under PBS guidelines for type 2 diabetes at the AMS. Some were supported in its commencement through diabetes shared care with RPAH Diabetes Centre. Follow-up was 12 months, and data was divided into responders where the HbA1c level decreased at least 0.5% NGSP points or non-responders. All accessible data is reported. Results: Of the 31 patients, average age was 56years and 35.5% were male with mean diabetes duration 11years. According to HbA1c criteria, 13 were responders (fall of 1.72±1.72% from 9.9%, mean±SD) and 18 failed therapy (rise of 0.65±0.80% from 8.6%, P=0.04 vs responders). No patient factor could be identified that co-segregated with difference in glycaemic outcome, including diabetes duration, starting HbA1c or documented adherence. Remarkably, in glycaemic non-responders, average body weight reduction was substantial at 9.12±4.12 kg. Body weight reduction in HbA1c responders was 6.7±4.9 kg (p=0.67). Degree of weight loss was not predicted by starting body weight which was 40.4±8.6 vs 40.2±6.71 kg/m2 for glycaemic responders vs non-responders. Overall, exenatide was well tolerated without pancreatitis ascribed to therapy, and nearly all patients dosed with 10μg s.c. bid. Conclusions: Glycaemic non-response to exenatide therapy is common in the indigenous population with a rate more than 50% and well above clinical trial data. However even in those who do not receive blood glucose improvement, mean body weight reduction is substantial, with at least 5kg weight loss being seen in the majority. The clinical response to this incretin mimetic in indigenous populations may be more predictable for body weight than for glycaemia.