Cessation or Reduction of Alcohol Consumption in Veterans: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of a GLP-1 Receptor Agonist Semaglutide in U.S. Veterans With Alcohol Use Disorder

Inclusion Criteria: * Veteran. * WHO risk drinking level of Very High or High in the 30 days prior to screening. * Current diagnosis of moderate or severe AUD (i.e., meeting at least 4 of 11 DSM-5 AUD criteria) based on semi-structured diagnostic exam. * Able and willing to provide informed consent. Exclusion Criteria: Medical and Psychiatric: * Type 1 diabetes. * Current serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or psychotic major depression, borderline or antisocial personality disorder, eating disorder). * Current DSM-5 diagnosis of a SUD (other than moderate-to-severe alcohol, any nicotine, or mild cannabis use disorders). * At the time of randomization, moderate-to-severe alcohol withdrawal (Clinical Institute Withdrawal Assessment for Alcohol (CIWA-AR) \>8). * BMI \<21 kg/m2. * Unstable body weight defined as \>5% change in body weight (documented or self-report; intentional or not) in the 90 days prior to randomization. * History of acute or chronic pancreatitis. * History of diabetic ketoacidosis. * History of proliferative diabetic retinopathy. * History of ascites, advanced liver fibrosis, compensated cirrhosis with portal hypertension, decompensated cirrhosis, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepatocellular carcinoma (HCC). * History of stage 3 fibrosis or stage 4 cirrhosis from a liver biopsy. * Presence of gastroparesis. * History of acute gallbladder disease in the prior 6 months. * History of advanced fibrosis or cirrhosis, including (but not limited to) transient elastography (liver stiffness) of \>12 kPa, FIB-4 2.67, ELF 9.8, MRE 3.63 kPa. * History of esophageal varices on endoscopy or imaging. * History of nodular liver, cirrhosis, splenomegaly, varices or splenic venous shunting or collaterals on prior imaging. * History or acute alcohol hepatitis (by liver biopsy or elevated bilirubin \> 1.5 times the upper limit of normal). * History of primary biliary cholangitis. * History of primary sclerosing cholangitis. * History of autoimmune liver disease. * History of hemochromatosis. * History of Wilson's disease. * History of alpha-10 antitrypsin-related liver disease. * History of drug-induced liver disease. * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2). * Acute high risk of suicide requiring hospitalization at the time of screening or randomization. * Medical, psychiatric, behavioral, or logistical conditions which, in the judgment of the Local Site Investigator (LSI) or Sub-Investigator (Sub-I), make it unlikely the participant can participate in or complete the 28-week active phase of the study. * Recent major cardiovascular event in the 90 days prior to randomization (myocardial infarction, stroke, New York Heart Association class IV heart failure, transient ischemic attack (TIA), or unstable angina. Laboratory * Hemoglobin A1c (HbA1c)\>10. * Estimated glomerular filtration rate (eGFR) \<30 mL/min. * Albumin \< 3.5 g/dl. * Aspartate aminotransferase (AST) \>3 the Upper Limit of Normal (ULN). * Alanine aminotransferase (ALT) \>3 the ULN. * Lipase \> 2 times the upper limit of normal. * Alkaline phosphatase \> 1.5 times the ULN. * Total bilirubin \> 1.5 times the ULN except with documented Gilbert's syndrome. * International Normalized Ratio (INR) \> 1.3 unless due to anticoagulation therapy. * Platelet count \<150,000/µL unless consistent with baseline and reflects the participant's habitual thrombocyte level, and there was no presence of portal hypertension. * Hepatitis B surface antigen positive. * Hepatitis C virus RNA positive - participants treated and cured of hepatitis C must have at least 2 years of negative testing. * Anti-HIV antibody positive test with uncontrolled or unstable treatment. * Positive urine drug screen for substances other than cannabis and prescribed medications. * Positive urine pregnancy test at screening in those considered of childbearing potential. Concurrent Treatments: * Current (within the past 30 days) use of pharmacotherapy for AUD (including oral or intramuscular naltrexone, acamprosate, disulfiram, topiramate). * Known history of prior hypersensitivity reaction to semaglutide, any of the product components, or any other GLP-1 analogue. * Current (within the past 30 days) use of the following medications with glucose-lowering properties: GLP-1 analogues; sulfonylurea; insulin and insulin products; dipeptidyl peptidase-4 (DPP-4) inhibitors; sodium-glucose cotransporter-2 (SGLT-2) inhibitors or other medications that may interact with semaglutide. * Recent changes in dose (within 2 months of randomization) of psychiatric medications (i.e., antidepressants, antianxiety, mood stabilizing). Other * Pregnant, actively breastfeeding, or female of childbearing potential who is unwilling to use a highly effective method of contraception as defined by the NIH \[67\]. * Currently enrolled in another therapeutic or investigational clinical trial. * Participant is incarcerated.