Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and the dual GIP/GLP-1 receptor agonist tirzepatide, have transformed the management of type 2 diabetes mellitus (T2DM) and obesity through once-weekly subcutaneous administration. While their efficacy and safety are well-established, the potential impact of administration timing-specifically, the day of the week-on clinical outcomes, adherence, and tolerability remains unexplored. Understanding whether specific days optimize therapeutic outcomes could inform personalized dosing strategies and improve long-term treatment success. Materials and Methods: We conducted a systematic literature review following PRISMA 2020 guidelines to identify studies examining the effect of weekly administration timing of semaglutide or tirzepatide on clinical outcomes in adults with T2DM or obesity. Comprehensive searches were performed across SciSpace (Deep Search, Basic Search, Full Text Search), Google Scholar, and PubMed databases through June 2026. Studies were screened using a two-stage process (abstract and full-text screening) with predefined PICO-based inclusion criteria. Data extraction focused on study design, population characteristics, administration timing, glycemic control, weight loss, adherence, and adverse events. Results: From 1471 identified records, 1000 unique papers underwent screening after deduplication and trimming. Three studies met inclusion criteria: the SUSTAIN 4 randomized controlled trial evaluating once-weekly semaglutide, a retrospective case series examining alternate-day oral semaglutide dosing, and an expert panel discussion on flexible dosing schedules. No studies directly compared different days of the week for injectable semaglutide or tirzepatide administration. Available evidence suggests that flexible dosing schedules may support adherence and tolerability without compromising glycemic control, though this suggestion derives primarily from indirect evidence and expert opinion rather than direct comparative clinical studies; direct comparative data on day-of-week effects are absent. Conclusions: Current evidence does not support a specific optimal day of the week for semaglutide or tirzepatide administration. The limited literature emphasizes flexible dosing schedules tailored to individual patient preferences and lifestyles to maximize adherence. Future prospective studies are needed to systematically evaluate whether administration timing influences clinical outcomes in real-world settings.
GLP-1 Therapies