Project Summary Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure. The only approved treatment to decelerate kidney disease progression in patients with ADPKD is tolvaptan, but its usage is limited due to frequent side effects affecting adherence. Thus, alternative interventions that may slow ADPKD progression hold considerable clinical importance. In line with the general population, body-mass index and insulin resistance have been increasing in patients with ADPKD. We have shown that visceral adiposity associates strongly with accelerated progression of early-stage ADPKD. Our R03-funded pilot study suggested that diet-induced weight loss may slow kidney growth (%? in height-adjusted total kidney volume [htTKV] by magnetic resonance imaging), and we are currently evaluating the efficacy of daily caloric restriction-induced weight loss for slowing ADPKD progression in a phase IIa clinical trial. However, the long-term adherence to lifestyle interventions is challenging, making pharmacological interventions a compelling adjunct or alternative. Moreover, our recently completed R21-funded study demonstrated that adults with ADPKD and preserved kidney function exhibited insulin resistance (via the gold- standard hyperinsulinemic-euglycemic clamps) and impaired kidney oxidative metabolism (via 11C-acetate PET), which were strongly associated with htTKV. These novel data suggest that targeting improvements in insulin sensitivity and kidney oxidative metabolism, in addition to weight loss, may slow ADPKD progression. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) were recently FDA-approved for the treatment of obesity and show promise in substantially reducing adiposity and improving insulin sensitivity. Additionally, evidence indicates that GLP-1RAs may transform CKD management by reducing nephropathy events in patients with and without diabetes, via effects extending beyond glycemic modulation, and in part via attenuated kidney inflammation and oxidative stress. However, GLP-1RAs have not yet been evaluated as a novel therapy for slowing ADPKD progression in patients with overweight/obesity. Thus, we propose a 24- month, phase II, randomized, placebo-controlled, double-blind clinical trial using a GLP-1RA in 126 adults with ADPKD and overweight or obesity to slow kidney growth (primary outcome). As a novel therapeutic in ADPKD, GLP-1RAs could transform the treatment landscape for patients. Specific Aim 1: Determine the effect of 24 months of GLP-1RA vs. placebo on kidney growth in adults with ADPKD and overweight/obesity. Specific Aim 2: Define changes in total body weight, adipose volume and function, insulin resistance, kidney oxidative metabolism, and inflammation after 24 months of GLP-1RA vs. placebo in adults. Specific Aim 3: Establish the safety and tolerability of GLP-1RA in adults with ADPKD and overweight/obesity.