Semaglutide Treatment in the Real-world for Fibrosis Due to NAFLD in Obesity and T2DM

Inclusion criteria: 1. Adult, age ≥ 40 and \< 80 years 2. Participant must meet at least one of following sets of conditions: 1. BMI ≥ 27 kg/m² OR 2. BMI ≥ 25 kg/m² AND presence of i) pre-diabetes (HbA1C ≥ 5.7) or ii) type 2 diabetes mellitus (T2DM), as defined by the American Diabetes Association (ADA) clinical practice recommendations. The ADA definition of T2DM is applicable if one of the following criteria is met: * Presence of diabetes symptoms (polyuria, polydipsia, polyphagia, increased fatigue, weight loss, blurred vision) and casual plasma glucose ≥ 200 mg/dL (11.1 mmol/L) * Fasting plasma glucose (FPG) ≥ 126 mg/dl (7.0 mmol/L) * Plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT)⁶⁸. If any of the above test results occur, testing should be repeated on a different day to confirm the diagnosis. OR • Hemoglobin A1C (HbA1C) ≥ 6.5% ⁶⁹. 3. FAST score ≥ 0.5 and VCTE ≥ 8.0 kPa; FAST score threshold based on data from MAESTRO-NASH trial⁴²; VCTE cutpoint based on AASLD guidelines for identification of patients with significant fibrosis risk. 4. Participants without a VCTE assessment in their medical record may qualify for the study if they have a FIB-4 ≥ 1.0, which is a cutpoint based on observations of patients with T2DM in Ajmera et al³⁰, and VCTE ≥ 8.0 kPa. 5. The subject is fully informed and willing and able to perform all the procedures specified in the protocol and has signed a written informed consent to participate Exclusion criteria: 1. Presence of regular and/or excessive use of alcohol, defined as \> 30 g/day for males and \> 20 g/day for females, for a period longer than 2 years at any time in the last 10 years 2. Evidence of cirrhosis or previously known cirrhosis, based on the results from previous liver biopsy or history of portal hypertension presented by ascites, hepatic encephalopathy or varices 3. VCTE ≥ 20 kPa 4. Platelet count ≤ 140,000 per Ml 5. Albumin \< 3.6 g/dL 6. INR \> 1.35, unless on coumadin for another indication 7. Serum creatinine \> 2.0 mg/dL 8. eGFR \< 30 mL/min/1.73 m² as defined according to the CKDEPI creatinine equation⁷⁰ 9. Use of other weight loss medications, including GLP1RA within the last 90 days 10. Greater than 10% weight loss in the prior six months 11. Known or suspected hypersensitivity to GLP1RA medications including semaglutide 12. History of bariatric surgery within the past 5 years or expected bariatric surgery 13. Evidence of other causes of chronic liver disease including: 1. Hepatitis B, as defined as presence of hepatitis B surface antigen (HBsAg). 2. Previous or current infection with Hepatitis C, as defined by presence of hepatitis C virus Ab in serum (anti-HCV Ab). 3. Autoimmune hepatitis, as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy. 4. Autoimmune cholestatic liver disorders, as defined by elevation of alkaline phosphatase and anti- mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis. 5. Wilson disease, as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease deficiency, as defined by alpha-1-antitrypsin phenotype and liver histology consistent with alpha-1-antitrypsin deficiency.