Sedentary behavior is engaging in activities in the seated or lying position that barely raise the energy expenditure above the resting metabolic rate and is a risk factor for obesity, diabetes, cardiovascular disease and mortality. However, it is unlikely that moderate/ vigorous intensity physical activities could be an effective replacement for sedentary activities for persons with CKD as most otherwise healthy Americans do not even reach the current goals for these activities. Therefore, in a NIDDK funded pilot and feasibility RCT (R21DK106574, PI: Beddhu), we tested, the feasibility of a `Sit Less, Interact, Move More (SLIMM)' intervention to replace sedentary activities with casual stepping activities in 106 participants with CKD. In the SLIMM group, the maximum decrease in sedentary duration (-43.0, 95% CI --69.0 to -17.0 min/day) and increase in stepping duration (15.5, 95% CI 6.9 to 24.1 min/day) and the number of steps/day (1265, 95% CI 518 to 2012) were seen at week 20 but attenuated at week 24. In post-hoc, descriptive analyses, higher baseline physical function as evidenced by 6-min walk distance and lower baseline body fat% measured by bio-impedance appeared to be associated with achieving SLIMM intervention goals in the SLIMM group. Based on our observations in the SLIMM pilot study, we propose a complex interplay between sedentary behavior, impaired physical function and obesity that leads to a vicious cycle that perpetuates sedentary behavior in CKD. Therefore, a successful intervention for sedentary behavior will need to incorporate co- interventions targeting obesity and impaired physical function. Specifically, we propose the addition of guided resistance training to increase physical function and semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist that has been shown to decrease adiposity and inflammation and improve health related quality of life. Herein we seek to implement SLIMM intervention alone for the first three months followed by a 9 month RCT of three equal groups of SLIMM + standard of care RT + placebo, SLIMM + guided RT + placebo and SLIMM + guided RT + oral semaglutide in 156 overweight or obese patients with moderate to advanced CKD. The designated primary endpoint is decrease in sedentary duration and the key secondary endpoint is six- minute walk distance. We will also explore the effects of the interventions on body-fat%, patient reported outcomes, lower extremity performance battery and markers of inflammation. There is a large pool of potential participants in the two institutions. The study is adequately powered to detect meaningful decrease in sedentary duration and other endpoints. This multi-disciplinary team of experienced investigators have a proven track record of successfully conducting RCTs. This proposal is feasible, innovative, and likely to yield results that will be informative. If the interventions decrease sedentary behavior in CKD, this trial will pave the way for larger RCTs ...