Three-Month Response Threshold as a Predictive Biomarker for Long-Term Weight Loss Sustainability in GLP-1 Receptor Agonist Therapy: A Real-World Cohort Study

Introduction and Objective: GLP1 receptor agonists demonstrate progressive attenuation of weight loss velocity over time, yet early predictors of long-term treatment failure remain undefined. We hypothesised that 3-month weight loss achievement serves as a critical decision point, predicting both peak efficacy and subsequent weight regain patterns Methods: This retrospective cohort study analysed 177 PwD initiating oral semaglutide (Rybelsus) with sequential follow-up over 18 months. Primary outcome was weight(wt) loss velocity deceleration pattern using paired t-tests for interval-to-interval comparisons (1→3→6→12→18 months). Secondary outcomes included percentage achieving wt loss thresholds (≥5%, ≥10%) at each interval vs. 3 month response and final outcomes. Results: Wt loss velocity demonstrated progressive deceleration: 1.99 kg/mth (0-1m), 1.55 kg/mth (1-3m, 22% slower, p<0.001), 0.59 kg/mth (3-6m, 62% slower, p<0.001), and 0.18 kg/mth (6-12m, 70% slower, p=0.037). Wt nadir occurred at 12 mths (-6.5% ± 6.1%), followed by significant regain beyond 12 mths (-5.0% ± 7.7%, representing 23% rebound, p=0.888). Critically, 3-mth achievement predicted final outcomes: 54.2% of patients achieved ≥5% loss at 3 mths versus 54.0% at 6 mths, demonstrating threshold stability. Cross-sectional analysis confirmed waning efficacy: baseline-adjusted wt loss remained significant at 6 mths (p=0.016) but lost significance by 12 mths (p=0.257), with increased population heterogeneity (SD progression: 6.1%→7.7%). Conclusion: Three-month weight loss achievement represents a critical therapeutic decision point for GLP-1 monotherapy. Patients failing to achieve ≥5% loss by 3 months demonstrate minimal additional benefit with continued monotherapy. These findings support evidence-based treatment algorithms incorporating mandatory 3-month efficacy assessment with pre-specified switching criteria to dual-incretin or combination approaches. Disclosure: B. Makkar: Speaker's Bureau; Current; Lilly, Novo Nordisk. Advisory Panel; Current; USV Private Limited. K. Soota: None. S. Singla: None. S. Patil: None.