Orlistat, phentermine/topiramate, and liraglutide are widely used obesity pharmacotherapies, but comparative data from Asian real-world settings remain limited. We compared their effects on body weight, glycemic control, and persistence. We performed a retrospective cohort study using electronic health records from a tertiary hospital in Korea. Adults prescribed orlistat, phentermine/topiramate, or liraglutide between 2018 and 2025 were included. The primary endpoint was percentage weight change at 6 months. Secondary endpoints were the proportions achieving ≥5% and ≥10% weight loss, weight change at 3, 6, and 12 months, change in HbA1c, and 12-month treatment persistence. We applied multivariable linear and logistic regression, linear mixed-effects models, propensity score-weighted models, and Kaplan-Meier and restricted mean survival time (RMST) methods. Among 1,910 treatment episodes, 505 involved orlistat, 777 phentermine/topiramate, and 628 liraglutide. Phentermine/topiramate showed greater mean percentage weight loss at 6 months than orlistat (adjusted difference, -1.59 percentage points;< 0.001), whereas liraglutide produced similar weight loss to orlistat. The odds of achieving ≥5% weight loss were higher with phentermine/topiramate than with orlistat (adjusted odds ratio, 2.21), while liraglutide showed a smaller effect. Liraglutide tended to reduce HbA1c more than orlistat, but this difference was attenuated after propensity score weighting. Twelve-month treatment persistence and RMST were lower with liraglutide than with the oral agents. In this real-world cohort, phentermine/topiramate achieved the most pronounced and sustained weight loss. Liraglutide and orlistat produced similar overall weight reduction, but liraglutide showed lower long-term persistence. p
