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Physical Fitness with Exercise and GLP-1 Receptor Agonist Treatment Alone or Combined After Diet-Induced Weight Loss: A Secondary Analysis of a Randomized Controlled Trial in Adults with Obesity - Sports Medicine Background Obesity is associated with impaired physical fitness, including physical functional performance and cardiorespiratory fitness, which affect health-related quality of life and mortality. Objective We aimed to investigate the efficacy of a moderate-to-vigorous intensity exercise program and glucagon-like peptide-1 receptor agonist treatment alone or in combination during weight maintenance for physical fitness. Methods This is secondary analysis of a randomized controlled trial involving 193 adults with obesity (age 18–65 years, body mass index 32–43 kg/m2) without diabetes mellitus who completed an 8-week low-calorie diet and were subsequently randomized (1:1:1:1 ratio) to: exercise plus placebo; glucagon-like peptide-1 receptor agonist liraglutide 3 mg once-daily plus usual activity; exercise plus liraglutide combined; or placebo plus usual activity. The exercise program was a combination of group sessions (interval-based indoor cycling followed by circuit training) and individual sessions of moderate-to-vigorous intensity, designed to meet the World Health Organization recommendations on physical activity for health. Exercise adherence was measured with sports watches and heart rate monitors. Key secondary endpoints related to physical fitness were changes from randomization to the end of treatment (weeks 0–52) in: (1) physical functional performance (time to ascend and descend an 11-step stairway twice); (2) cardiorespiratory fitness (peak oxygen consumption normalized to fat-free mass); and (3) muscle strength (isometric knee extensor peak torque). Results Participants randomized to exercise performed a median 2.65 session/week (116 min/week at 79% of maximum heart rate) with no significant difference between those who received placebo or liraglutide. Compared with liraglutide alone, the combined treatment decreased time to complete a stair climb test by 1.2 s [95% confidence interval 0.6–1.9] (corresponding to 8.6%) and improved peak oxygen consumption by 3.0 mL/min/kg fat-free mass [95% confidence interval 0.5–5.5]. Exercise alone led to similar benefits, whereas liraglutide alone did not improve physical fitness. Compared with placebo (− 7.8%), relative muscle strength (strength normalized to body weight) was higher with exercise (− 0.4%), liraglutide (+ 1.0%), and the combined treatment (+ 3.3%) because of lower weight and preserved absolute strength. Conclusions Structured exercise combined with glucagon-like peptide-1-based obesity pharmacotherapy led to clinically meaningful improvements in physical functional performance and cardiorespiratory fitness, in contrast to pharmacotherapy alone. Clinical Trial Registration EudraCT number, 2015-005585-32; https://bit.ly/4k7xfiH number, NCT04122716. https://bit.ly/4qITEVS