Fibrosis Lessens After Metabolic Surgery

Eligibility Criteria

• 1. Is a candidate for general anesthesia
• 2. Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines
• 3. Is ≥18 and ≤70 years old
• 4. Has a BMI ≥35 and ≤60 kg/m\^2 at the time of first study visit
• 5. FIB-4 ≥ 1.3
• 6. At least one of the following 5 criteria suggesting presence of advanced fibrosis:
• * LSM ≥ 12 kPa by VCTE using FibroScan
• * LSM ≥ 12 kPa by SWE
• * LSM ≥ 1.7 m/s by ARFI
• * LSM ≥ 3.63 kPa MRE
• * ELF score ≥ 9.8
• 7. Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication (including insulin but not semaglutide or tirzepatide or liraglutide) for at least 3 months prior to entry, with glycated hemoglobin (HbA1c) ≤12%.
• 8. Self-reported stable weight in 3 months before the first study visit (no weight change \>5% within 3 months prior to the first study visit)
• 9. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study.
• 10. Can understand the options and comply with the requirements of each arm, including one liver biopsy performed during the screening period (if no adequate biopsy within 12 months before screening is available) and one liver biopsy after 2-years.
• 11. Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential.
• 12. Women of childbearing age must agree to use reliable method of contraception for 2 years.
• 1. Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic):
• 1. Hepatitis B as detected by presence of hepatitis B surface antigen (HBsAg)
• 2. Hepatitis C as detected by presence of hepatitis C virus (HCV) RNA (in case the screening test for hepatitis C is positive, the confirmative test is decisive)
• 3. Autoimmune liver disease as diagnosed by antibodies or compatible liver histology
• 4. Primary biliary cirrhosis as defined by the presence of at least 2 criteria (elevated alkaline phosphatase, presence of anti-mitochondrial antibody, and histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts)
• 5. Primary sclerosing cholangitis
• 6. Wilson's disease as diagnosed by low ceruloplasmin or compatible liver histology
• 7. Alpha-1-antitrypsin deficiency as diagnosed by alpha1-antitrypsin level or liver histology
• 8. Hemochromatosis as diagnosed by HFE mutations (C282Y, H63D), ferritin and transferrin saturation levels, or presence of 3+ or 4+ stainable iron on liver biopsy
• 9. Drug-induced liver disease diagnosed by medical history
• 10. Known bile duct obstruction
• 11. Suspected or proven liver cancer
• 2. Treatment with semaglutide, tirzepatide, or liraglutide for obesity or for T2DM \<90 days before the first study visit
• 3. Treatment with vitamin E (at doses ≥800 IU/day), pioglitazone, obeticholic acid, or resmetirom \<90 days before the first study visit
• 4. Type 1 diabetes or autoimmune diabetes
• 5. Known cases of human immunodeficiency virus infection
• 6. Prior bariatric and metabolic surgery of any kind
• 7. Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery
• 8. Thoracic, abdominal, pelvic, or obstetric-gynecologic surgery within 6 months prior to signing the consent
• 9. Any other surgery requiring general anesthesia within 6 weeks prior to signing the consent
• 10. History of solid organ transplant
• 11. Severe pulmonary disease defined as FEV1 \< 50% of predicted value
• 12. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
• 13. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
• 14. Classified as New York Heart Association Class IV
• 15. Left ventricular ejection fraction \<25% at the time of screening
• 16. Myocardial infarction, unstable angina, stroke, transient ischemic attack, heart surgery, coronary stent placement in the past 6 months
• 17. Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis
• 18. Presence of large hiatal hernia (\>7 cm)
• 19. Presence of Crohn's disease
• 20. Psychiatric disorders including (but not limited to) dementia, active psychosis, severe depression requiring 3 or more medications, history of suicide attempts, active alcohol, or substance abuse within the previous 12 months that in the opinion of the investigators could disqualify the patient from metabolic surgery
• 21. Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures
• 22. Breastfeeding
• 23. Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal cell cancer of the skin)
• 24. Anemia defined as hemoglobin less than 9 g/dL
• 25. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)
• 26. Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis
• 27. Clinical judgment that life expectancy is less than 3 years
• 28. Use of investigational therapy within 3 months prior to signing the consent
• 29. History of pancreatic carcinoma
• 30. Acute pancreatitis \< 180 days before screening
• 31. History or presence of chronic pancreatitis
• 32. History of thyroid cancer
• 33. Presence of concerning thyroid nodule
• 34. Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) \> 6.0 mIU/L or \< 0.4 mIU/L before the first study visit
• 35. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• 36. Evidence or history of ascites or spontaneous bacterial peritonitis
• 37. Evidence or history of hepatic encephalopathy
• 38. Evidence or history of variceal bleeding
• 39. Evidence or history of portosplenic vein thrombosis
• 40. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to the first study visit. Defined as more than 14 units/week for females (\>1 drink per day) and more than 21 units/week for males (\>2 drinks per day) on average, where one unit of alcohol is equivalent to a 12-oz beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor.
• 41. Treatment with medications (for more than 14 consecutive days) with known effect on liver steatosis (e.g., treatment with systemic corticosteroids \[oral or intravenous\], methotrexate, tamoxifen, valproic acid, amiodarone, or tetracycline) in the 3 months prior to the first study visit (or historical liver biopsy).
• 42. ALT or AST or Alkaline phosphatase \>200 U/L
• 43. Recurrent major hypoglycemia or hypoglycemic unawareness
• 44. Inability to safely obtain a liver biopsy
• 45. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study
• 46. Unable to understand the risks, benefits, and compliance requirements of study
• 47. Lack capacity to give informed consent
• 48. Plans to move outside the primary location of study (country) within the next 24 months
• 49. Known or suspected allergy to semaglutide, tirzepatide, liraglutide, excipients, or related products
• 50. Previous participation in this trial and got randomized to one of the study groups but did not proceed.
• 51. Hospitalization due to COVID-19 within 2 months prior to screening.
• 52. Platelet count \<100,000
• 53. International Normalized Ratio (INR) \>1.7
• 54. Child-Pugh score B or C
• 55. MELD score ≥12
• 56. Upper endoscopy showing gastroesophageal varices
• 57. Upper endoscopy showing more than mild portal hypertensive gastropathy
• 58. Liver vascular ultrasound (duplex ultrasonography) showing significant portal hypertension characterized by dilated portal vein (\>13 mm), biphasic or reverse flow in the portal vein, enlarged paraumbilical veins, splenorenal collaterals, or dilated left and short gastric veins.
• 59. Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites
• 60. HVPG ≥ 10 mmHg (if available historically or if measured at the time of de novo liver biopsy