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
Susumu Inamine, Yasunori Uesato ABSTRACT
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 2 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.