Vutiglabridin overcomes the GLP-1 RA-associated weight-loss plateau to achieve normal body weight.

Abstract

Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective for body weight reduction, there remains a critical unmet need for complementary strategies that drive selective fat loss and sustain long-term weight reduction. This study aimed to investigate whether Vutiglabridin, a novel oral small-molecule anti-obesity drug, complements GLP-1 RAs to enhance therapeutic efficacy by selectively reducing fat mass and achieving normal body composition. 6-week-old mice were fed a high-fat diet (60 kcal% fat) for 11 weeks to generate mice with diet-induced obesity (DIO) and then treated with GLP-1 RAs (Semaglutide, Liraglutide, or Exenatide) either alone or in combination with Vutiglabridin for 3-4 weeks. Body weight, food intake, fat mass, and lean mass were evaluated during treatment. For the drug discontinuation study, mice were administered Vutiglabridin, Semaglutide, or the combination for 4 weeks, after which treatment was withdrawn on Day 28 and body weight regain was monitored for 21 days. In DIO mice treated with Semaglutide, weight loss attenuated, and body weight was maintained at a constant level after 2 weeks. In contrast, co-administration of Vutiglabridin overcame this attenuation of efficacy, enabling continuous weight reduction and achieving normal body composition. Vutiglabridin also resolved the diminishing weight-loss effect when combined with comparatively less potent appetite-suppressing GLP-1 RAs, including liraglutide and exenatide. In addition to normalizing body composition, Vutiglabridin mitigated the body weight and fat-mass regain that occurs following Semaglutide discontinuation. These findings demonstrate that Vutiglabridin can normalize body composition in combination with multiple GLP-1 RAs, highlighting its potential as a novel therapeutic option for obesity treatment.