GLP-1 Receptor Agonist Therapy for Obesity Under Japan's Optimal Use Guideline: A Prospective Real-World Study of Lifestyle Pre-Treatment, Time-Limited Treatment Cap, and Post-Cessation Regain.

AIMS: Japan's optimal use guideline restricts insurance-reimbursed GLP-1 receptor agonist (GLP-1 RA) therapy for obesity to patients completing a mandatory 6-month lifestyle intervention, caps treatment at 68 weeks (semaglutide 2.4 mg) or 72 weeks (tirzepatide), and mandates subsequent washout. We evaluated the clinical implications of this regulated program in a real-world cohort of patients with obesity treated with semaglutide or tirzepatide, with particular attention to pre-treatment weight change during the mandated lifestyle phase, on-treatment response, and post-cessation weight regain. MATERIALS AND METHODS: We prospectively followed 104 patients with obesity without type 2 diabetes (45 primary, 59 post-metabolic/bariatric-surgery rescue) treated with semaglutide (n = 43) or tirzepatide (n = 61) under Japan's optimal use guideline. Both cohorts qualified for GLP-1 RA under the same insurance eligibility criteria (BMI ≥ 27 kg/m with obesity-related comorbidities). Body weight was recorded bimonthly from 6 months before drug initiation through the post-cessation washout phase. Outcomes included percent body weight change from baseline and rates of weight loss and regain across phases. RESULTS: During the mandated lifestyle phase, the rescue cohort gained weight (+2.28 ± 4.16 kg; 69% gained weight), while the primary cohort remained essentially stable (-0.65 ± 5.51 kg; p = 0.004). Once GLP-1 RA was initiated, % body weight change trajectories were comparable between cohorts from month 4 onward (month 6: -11.8% vs. -10.8%, p = 0.57). Aggregate % body weight change reached a partial plateau by months 10-14 (-16.3%, -16.1%, -15.5%) and was -16.0% at the treatment endpoint (month 16, n = 30, all semaglutide-treated). After mandated cessation, 95% (21/22) of patients regained weight by 2 months, and 83% (10/12) by 6 months. Indexed to month -6, mean change reverted from -14.4% at month 16 to -7.0% at month 22, indicating substantial loss of achieved treatment benefit. CONCLUSIONS: Under Japan's current regulatory framework, GLP-1 RAs produced comparable weight loss in primary and rescue cohorts sharing the same eligibility criteria. Phase-specific observations-pre-treatment weight gain in the rescue cohort and achieved treatment effect that reverted rapidly after mandated cessation-provide a real-world basis for examining whether mandated treatment cessation is compatible with the chronic nature of obesity.