In this study, semaglutide will be compared to placebo (a look-alike inactive substance, a "sugar pill") to determine if its use will prevent weight gain after liver transplantation (LT). In addition, researchers will be testing to determine if semaglutide prevents the development of Non-Alcoholic Fatty Liver Disease (NAFLD) after transplant through Magnetic Resonance Imaging (MRI) and laboratory results.

Weight gain following LT is common and a risk for cardiovascular disease and development of NAFLD. Developing NAFLD following LT can lead to patients developing scar tissue in the graft (transplanted liver), and graft-cirrhosis. These events can limit the benefit of the transplanted liver graft and reduce the benefit of LT as a therapy. Current weight management strategies have not been successful at the prevention of these events in most patients. This highlights a substantial unmet need for effective treatment to prevent or reduce post-LT weight gain and highlight the importance of new treatment strategies for reducing illness, death, and healthcare cost associated with post-LT weight gain.

The purpose of this research study is to test the safety, tolerability, and effectiveness of semaglutide when used to prevent weight gain after liver transplant. Semaglutide is a drug that has been approved by the U. S. Food and Drug Administration (FDA) for treatment of obesity and Type 2 Diabetes.

Semaglutide, has shown to be effective for not only weight loss but also long-term weight maintenance. Semaglutide has also shown to be helpful in treatment of nonalcoholic steatohepatitis (NASH) in the non-transplant population. This medication also is used to control blood sugar and prevent cardiovascular disease, which contributes to poor outcomes in LT recipients. Thus, the purpose of the present study is to determine if use of semaglutide early after LT can (1) reduce weight gain and (2) prevent development of NAFLD following LT.

Inclusion Criteria:

• Male or female age 18-75 years who received LT for any indication (i.e. NASH, hepatitis C, alcohol-induced cirrhosis, autoimmune hepatitis, etc.)
• Liver transplant surgery within 8-24 weeks prior to randomization
• Fasting glucose > 125 mg/dL or presence of diabetes (HbA1c≥6.5% or use of diabetes medications) or pre-diabetes (HbA1c >5.7%)
• Ability to provide informed consent
• Discharged from the hospital following LT surgery
• Tolerating diet
• Normal graft function* (determined by treating hepatologist/surgeon based on clinical status and hepatic panel)
• Stable immunosuppression according the VCU (Virginia Commonwealth University) post-LT protocols ** (i.e. calcineurin inhibitors + mycophenolate)
• Eligible female patients will be (1) non-pregnant, evidenced by a negative urine pregnancy test, (2) non-lactating, (3)surgically sterile or post-menopausal, or they will agree to continue to use an accepted method of birth control during the study

Exclusion Criteria:

• BMI≤ 27kg/m2
• GFR (Glomerular Filtration Rate) ≤ 25 ml/min/1.73m2
• Type 1 autoimmune diabetes (by anti-GAD (glutamic acid decarboxylase) or history of ketoacidosis)
• History of gastroparesis
• Familial or personal history of medullary thyroid cancer or MEN (Multiple Endocrine Neoplasia) 2
• History of pancreatitis
• History of active malignancy post- LT with the exception of non-melanoma skin cancers
• History of uncontrolled or unstable diabetic retinopathy or maculopathy
• Acute cellular rejection
• Hepatic artery thrombosis
• Medical non-compliance
• Active treatment with GLP (glucagon-like peptide)-1RA (receptor agonist) or SGLT (sodium-glucose cotransporter)-2 inhibitors at time of screening
• History of hypersensitivity to semaglutide or its excipients
• Women who are nursing, pregnant, or planning to become pregnant during the study, or are not using adequate contraceptive measures