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Introduction Reducing dosing frequency may lower treatment burden and improve persistence and adherence. This retrospective, observational study assessed persistence and adherence in patients with type 2 diabetes (T2D) initiating once-weekly or daily injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in US clinical practice. Methods The study used data from adults (≥ 18 years) with T2D who were included in the IBM MarketScan Explorys Claims-EMR Data Set for ≥ 180 days pre-index and ≥ 365 days post-index, were GLP-1 RA and insulin naïve at first claim (index date) for once-weekly or daily injectable GLP-1 RAs (follow-up: index date + 365 days), and were propensity score (PS) matched 1:1 by baseline characteristics. Persistence, defined as the stay time, was assessed using Kaplan–Meier analysis and Cox proportional hazards models. Adherence was defined as a proportion of days covered of 0.8 or greater. To assess whether patients with more advanced disease would benefit from long-acting treatments, patients were matched to the baseline characteristics of basal insulin initiators using inverse probability of treatment weighting (IPTW). Results The PS-matched cohorts (n = 784 each) had similar baseline characteristics. Once-weekly regimens were associated with significantly higher persistence than daily treatments (median stay time: 333 vs 269 days; hazard ratio 0.80 [95% confidence interval 0.71, 0.90]; p, Plain Language Summary For people who take medication over a prolonged time, less frequent doses are often more convenient. This can help people to continue with treatment for as long as prescribed (persistence) and to take their medication as prescribed (adherence). This study examined persistence and adherence in people with type 2 diabetes who started treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The GLP-1 RAs in this study are injected under the skin using a small needle. Some types are given daily and others are given once weekly. We used a US database of medical records to identify people with type 2 diabetes who had been prescribed these medications and split them into two groups (784 people each) with similar characteristics. One group had received once-weekly GLP-1 RAs and the other group had received daily GLP-1 RAs. We found that the once-weekly group continued taking their medication for longer (333 days) than the daily group (269 days). People in the once-weekly group were also 20% less likely to stop the treatment too early than those in the daily group. More people in the once-weekly group took their medication as prescribed over 1 year compared with the daily group. The once-weekly group also had larger reductions in blood sugar levels after 1 year than the daily group. People who took their medication as prescribed had the greatest improvements in blood sugar levels. Our results suggest that GLP-1 RAs that are injected less frequently can help people to take their medication as prescribed. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01189-6.