This study examines real-world, evidence-based comparisons of persistence and adherence to daily versus weekly glucagon-like peptide 1 (GLP-1) receptor agonists for the treatment of type 2 diabetes (T2D).This retrospective observational study used U.S. insurance claims data to compare persistence and adherence to GLP-1 receptor agonists in patients with T2D initiating once weekly (QW) exenatide or daily liraglutide over a 6-month follow-up period. Eligible patients had ≥2 diagnoses of T2D, were 18 years of age or older, initiated a new prescription of either the index drug between February 1, 2012 (market availability launch date of exenatide QW) and March 31, 2013, and had ≥6 months continuous eligibility in the pre- and postindex periods. A 1:1 propensity score match was used to account for selection bias. Outcome measures included persistence as measured by the percentage of patients who continued to take the index drug over an index period of 182 days with an allowable gap of 60 days and adherence as measured by the proportion of days covered (PDC). The percentage of patients achieving PDC ≥0.8 and ≥0.9 was also calculated.There were no significant differences between baseline characteristics after propensity score matching. Each matched cohort included 12,306 patients. The overall persistence observed with liraglutide was 66% compared with 63% for exenatide QW. The mean (SD) PDC adherence during the 6-month follow-up period was 0.694 (0.309) for the exenatide QW cohort and 0.689 (0.286) for the liraglutide cohort. The PDC threshold of ≥0.8 during the 6-month follow-up period was met by 6309 (51%) and 5820 (47%) patients in the exenatide QW and liraglutide cohorts, respectively. For the exenatide QW cohort, 76% of patients treated previously with BID exenatide continued treatment in the 6-month follow-up period compared with 59% who were not previously treated with exenatide BID. For the liraglutide cohort, 77% of previous exenatide BID patients continued treatment versus 63% of patients who were not previously treated with exenatide BID.These results reveal slight differences in persistence and adherence rates in patients receiving exenatide QW versus patients receiving liraglutide daily that vary by outcome and previous incretin-based therapy used. Differences may be due to dosing device differences for exenatide QW and liraglutide, which, in the case of liraglutide, allows the opportunity for daily self-titration dosing. Implications of these findings for clinical practice are that persistence is determined by the broader context of treatment and medications being used and should be considered when prescribing GLP-1 receptor agonists.