Abstract Body: Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1) promote weight loss, improve diabetes, and reduce cardiovascular events in obesity. While physical activity (PA) should be integral to weight loss interventions, the effectiveness of GLP-1, with weight loss in the range of 15-20%, may remove incentives to exercise. Cardiorespiratory fitness (fitness), a marker of habitual PA and health outcomes, may increase with weight loss. GLP-1 effects on PA and fitness are not clear. Thus, in a preventive medicine cohort, the question of whether GLP-1 use is associated with changes in fitness was evaluated.

Methods: A cohort of 205 generally healthy men and women reported leisure-time PA and completed treadmill exercise testing to estimate fitness before and during GLP-1 use (+GLP-1), 2009-2024. A similar cohort of 10,903 men and women did not report GLP-1 use (-GLP-1) in the same period. A repeated measures growth model provided estimates of the group difference in fitness changes adjusted for sex, age, time between visits, PA, and weight.

Results: Before treatment in +GLP-1, 89% were overweight/obese, 19% were diabetic, and 1% had prior cardiovascular events (versus 64%, 2%, and 1% in -GLP-1). The mean (SD) baseline age was 52.0 (8.5) years in +GLP-1 and 52.3 (9.7) in -GLP-1. In +GLP-1, the mean follow-up was 2.6 years (versus 2.5 in -GLP-1). Mean body mass index decreased 2.1 kg/m2 in +GLP-1 versus no significant change in -GLP-1. Mean glucose also decreased in +GLP-1 (from 108.4 mg/dL to 97.5 mg/dL, p<0.001) but no change in -GLP-1. Mean PA was largely unchanged in both groups (+50 versus +30 MET-minutes/week, p=0.8).

Mean unadjusted fitness was stable at 9.1 METs in +GLP-1, p=0.5, and decreased from 11.0 to 10.7 METs in -GLP-1, p<0.001 (group difference in changes p<0.001). Results were similar when adjusted for sex, age, time between visits, and PA changes. However, when also adjusted for weight change, mean fitness fell 0.5 METs in +GLP-1 versus 0.2 METs in -GLP-1, p<0.001. Fitness increased less in +GLP-1 than in -GLP-1 whether weight was lost or gained.

Conclusions: Fitness changes in +GLP-1 were largely mediated by weight loss. While GLP-1 use was associated with greater weight loss, fitness outcomes were worse in +GLP-1 than in -GLP-1 with similar weight changes. Healthcare providers should prescribe and monitor PA along with GLP-1 receptor agonists, as tolerated by patient’s overall status, to improve weight loss and fitness.