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As the first oral GLP-1 receptor agonist (GLP-1RA), oral semaglutide (sema) may facilitate increased access to the benefits of GLP-1RA therapy in broader care settings. Understanding the management of GLP-1RA therapy when intolerability occurs, including gastrointestinal (GI) adverse events (AEs), is important to overcome potential barriers to treatment persistence. The PIONEER 6 trial (NCT02692716; N=3183) examined the efficacy and safety of oral sema in patients (pts) with T2D either ≥50 years with established cardiovascular (CV) or kidney disease, or ≥60 years with CV risk factors. In total, 27% of pts stopped taking oral sema at least once during the trial due to an AE, but only 12% permanently discontinued due to an AE. We thus evaluated medication management strategies within PIONEER 6 to assess their role in supporting treatment continuation. Pts on oral sema underwent dose escalation starting at 3 mg, increasing to 7 mg after 4 weeks, and 14 mg after 8 weeks. Investigators were permitted to reduce the dose if AEs developed and to re-escalate the dose once symptoms had resolved or diminished. Pts were educated as needed to address GI tolerability issues throughout the trial. Pts who discontinued treatment because of an AE were encouraged to resume treatment once willing or once the AE had ceased. The time off oral sema was considered a treatment pause. If treatment pauses were >21 days, re-escalation from a lower dose was recommended to mitigate GI AEs. Discontinuation of oral sema (temporary and permanent) mostly occurred during the initial dose escalation period. In total, 23% of pts receiving oral sema had ≥1 treatment pause, the majority of whom (72%) had just one pause. The median duration of treatment pause was 21 (IQR 7-51) days. Importantly, 75% of pts restarted oral sema after the first AE-related treatment discontinuation. These data highlight the role of treatment pauses, flexibility, and education in mitigating potential AEs to support treatment persistence on GLP-1RAs. Disclosure V. R. Aroda: Consultant; Self; Applied Therapeutics, Duke, Novo Nordisk, Pfizer Inc., Sanofi, Employee; Spouse/Partner; Janssen, Merck, Research Support; Self; Applied Therapeutics, Eli Lilly and Company, Fractyl, Medpace, Medpace, Novo Nordisk, Premier, Sanofi, Stock/Shareholder; Spouse/Partner; Janssen, Merck. R. Bauer: Employee; Self; Novo Nordisk A/S. A. L. Davies: Employee; Self; Novo Nordisk. E. B. Kreiner: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. P. J. Lin: Advisory Panel; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Napp Pharmaceuticals, Novo Nordisk A/S, Sanofi, Consultant; Self; ADOCIA, Speaker’s Bureau; Self; Bayer AG, Medscape, WebMD LLC. Funding Novo Nordisk A/S