Low‐Dose Tirzepatide for Obesity: Comparative Efficacy of 2.5 mg Versus 5 mg in Non‐Diabetic Japanese Adults

ABSTRACT Background Obesity is a major global health issue. While tirzepatide demonstrates robust weight reduction in clinical trials, data comparing low maintenance doses (2.5 vs. 5 mg) in non‐diabetic adults with obesity remain limited. This study evaluated the comparative efficacy and safety of 2.5 versus 5 mg tirzepatide combined with lifestyle intervention. Methods This multicentre, prospective, non‐randomised cohort study enrolled non‐diabetic Japanese adults (18–65 years) with BMI ≥ 30 kg/m 2 or ≥ 27 kg/m 2 with comorbidities. Patients initiated tirzepatide at 2.5 mg weekly; after 4 weeks, the dose was maintained at 2.5 mg or increased to 5 mg based on shared decision‐making. All participants received standardised dietary and exercise counselling. The primary outcome was the proportion achieving BMI < 25 kg/m 2 or > 15% body weight reduction at 6 months. Results Of 112 participants analysed (58 on 2.5 mg, 54 on 5 mg), baseline characteristics were well balanced (mean BMI 30.8 kg/m 2 ). At 6 months, the primary outcome was achieved in 62.1% of the 2.5 mg group and 63.0% of the 5 mg group (HR 0.93, 95% CI 0.58–1.49; p = 0.772). Mean percent weight loss was −15.3% and −16.1%, respectively ( p = 0.563), with similar reductions in BMI, skeletal muscle mass, and bone mass. Adherence to dietary therapy was excellent in both groups (96.4%), while exercise adherence was 37.5%. Adverse events were more frequent with 5 mg (50% vs. 35%), primarily gastrointestinal symptoms. Conclusion In non‐diabetic Japanese adults with obesity, 2.5 and 5 mg tirzepatide combined with lifestyle modification yielded similar weight loss at 6 months, with better tolerability at the lower dose. These findings support the potential utility of low‐dose tirzepatide strategies in real‐world practice.