Introduction and Objective: GLP-1RA therapies induce weight loss primarily through appetite suppression but do not reduce adipocyte number and have limited effects on abdominal subcutaneous fat. After treatment discontinuation, recovery of appetite may promote adipocyte re-expansion, weight regain, and increased visceral fat accumulation. This study evaluated whether combining tirzepatide with CBL-514 improves durability of weight loss after tirzepatide discontinuation. Methods: Diet-induced obesity rats on a high-fat diet were assigned to tirzepatide alone, CBL-514 alone, tirzepatide plus CBL-514, or a control group. Tirzepatide was initiated first, with CBL-514 added one week later and continued for four weeks in combination. Tirzepatide was then discontinued, while CBL-514 was continued for two additional weeks, followed by one week of observation. Outcomes included changes in fasting body weight, weight regain after tirzepatide discontinuation, subcutaneous and visceral adipose tissue depots, hepatic lipid parameters, insulin resistance (HOMA-IR), and safety evaluation. Results: At tirzepatide off-treatment, fasting body-weight reduction was -14.5% with tirzepatide alone and -21.8% with combination group. Three weeks after tirzepatide discontinuation, weight regain was +55.9% in the tirzepatide alone and +25.2% in the combination group. In the tirzepatide alone compared with combination group, subcutaneous fat mass was reduced by -15.4% versus -43.5%; total visceral fat mass was reduced by -8.9% versus -41.6%. Improvements in hepatic lipid measures and insulin resistance were greater in the combination group. Conclusion: Combination of tirzepatide with CBL-514 resulted in more profound weight loss, substantially enhanced subcutaneous and visceral fat reduction, and markedly attenuated post-treatment weight regain compared with tirzepatide alone, supporting adipocyte number reduction as a complementary strategy to incretin-based therapy. Disclosure Y. Ling: Board Member; Current; Caliway Biopharmaceuticals Co., Ltd. M. Liang: Employee; Current; Caliway Biopharmaceuticals Co., Ltd. Y. Liu: Employee; Current; Caliway Biopharmaceuticals Co., Ltd. W. Garvey: Advisory Panel; Current; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Novo Nordisk. Research Support; Current; Novo Nordisk. Advisory Panel; Ended; Pfizer Inc. Advisory Panel; Current; Fractyl Health, Inc., Zealand Pharma A/S. Research Support; Current; Zealand Pharma A/S. Advisory Panel; Current; Genentech, Inc. Research Support; Current; Genentech, Inc. Advisory Panel; Current; TERNS Pharmaceuticals. Research Support; Current; TERNS Pharmaceuticals. Advisory Panel; Current; Neurocrine Biosciences, Inc. Advisory Panel; Ended; Keros Therapeutics. Advisory Panel; Current; Gan Ended; Corcept Therapeutics. Advisory Panel; Current; Metsera, Graviton, AbbVie Inc., Regeneron Pharmaceuticals Inc., Madrigal Pharmaceuticals, Inc. Research Support; Current; Viking Therapeutics, Kaleira. A. Sharma: Advisory Panel; Current; Caliway Biopharmaceuticals Co., Ltd. K. Huang: Advisory Panel; Current; Caliway Biopharmaceuticals Co., Ltd. J. Xu: Employee; Current; Caliway Biopharmaceuticals Co., Ltd.
Ling et al. (Fri,) studied this question.