The objective of this systematic review was to assess the published literature on the effectiveness of exenatide twice daily (exenatide) in clinical practice, specifically its effects on haemoglobin A1c (A1C), fasting glucose (FG), weight, systolic blood pressure (SBP), medication use, hospitalization and cardiovascular disease (CVD) outcomes. A systematic literature search using the MEDLINE database of English language literature published between January 2005 and May 2011 was performed. The review included retrospective or prospective observational studies that included 100 or more patients per treatment group. A total of 15 studies meeting the inclusion criteria were identified. The studies revealed significant reductions of −0.4 to −0.9% in A1C, −10 mg/dl in FG, −2 to −11 kg in body weight and −2 to −11 mmHg in SBP. Statistically significant reductions in the use or dosage of either oral glucose-lowering medications or insulin after initiating exenatide treatment were found in every observational study that assessed medication changes, including reductions in dosage of up to 75% in sulphonylureas dosages, 22% in metformin, 66% in thiazolidinediones (TZD) or TZD combination therapy and 75% in prandial insulin. Exenatide-treated patients experienced significantly lower rates of all-cause and CVD-related hospitalization and CVD events than patients treated with other therapies overall. In this review of observational studies, exenatide initiation was associated with significant reductions in clinically relevant outcomes. Improvements in A1C, FG, weight and SBP in the observational studies in this review were consistent with improvements observed in controlled clinical trials.