FLAMES

Entry into the study would require that the patient:

1. Is a candidate for general anesthesia

2. Is eligible for metabolic surgery (RYGB or SG) based on the ASMBS/IFSO 2022 guidelines

3. Has insurance coverage for metabolic surgery (the requirements may vary in each country)

4. Is ≥18 and ≤75 years old at the time of signing the informed consent

5. Has a BMI ≥35 and ≤70 kg/m2 at the time of first study visit

6. FIB-4 ≥ 1.3

7. At least one of the following 5 criteria suggesting presence of advanced fibrosis:

8. 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%.

9. Self-reported stable weight in 6 months before the first study visit (no weight loss >10% within 6 months prior to the first study visit)

a. In patients with a historical noninvasive tests or liver biopsy, weight loss of no more than 10% is allowed from 6 months prior to the historical tests until the first study visit

10. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study

11. 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

12. Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential.

13. Women of childbearing age must agree to use reliable method of contraception for 2 years

8.2 Exclusion Criteria

Patients who meet the following criteria will be excluded from the study:

1. Known history of other chronic liver diseases (drug induced, viral hepatitis, autoimmune, and genetic):

2. Weight change >10% within 6 months prior to the first study visit or prior to the historical liver biopsy

3. Treatment with semaglutide, tirzepatide, or liraglutide (for obesity or for T2DM) <90 days before the first study visit.

• However, patients are allowed to participate if they have been on a low dose (or are on older generation GLP-1 agonists) and have lost less than 10% of their body weight since starting the medication.

4. Type 1 diabetes or autoimmune diabetes

5. Known cases of human immunodeficiency virus infection

6. Prior bariatric and metabolic surgery of any kind

• Reversed procedures such as gastric band or intragastric balloon that have been removed at least 3 months prior to the first study visit are allowed.

7. Prior complex foregut surgery including any esophageal and gastric surgeries, anti-reflux procedures, biliary diversion, and complex trauma surgery

8. Any surgery requiring general anesthesia within 1 month prior to signing the consent

9. History of solid organ transplant

10. Severe pulmonary disease defined as FEV1 < 50% of predicted value

11. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)

12. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V

13. Classified as New York Heart Association Class IV

14. Left ventricular ejection fraction <25% at the time of screening

15. Myocardial infarction, unstable angina, stroke, heart surgery, coronary stent placement in the past 6 months

16. Chronic renal insufficiency with eGFR below 30 mL/min/1.73 m2, or being on dialysis

17. Presence of large hiatal hernia (>7 cm)

18. Presence of Crohn's disease

19. 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

20. Pregnancy, the intention of becoming pregnant, or not using adequate contraceptive measures

21. Breastfeeding

22. Diagnosis of malignancy within the preceding 3 years (except squamous cell and basal cell cancer of the skin)

23. Anemia defined as hemoglobin less than 9 g/dL

24. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)

25. Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis

26. Clinical judgment that life expectancy is less than 3 years

27. Use of investigational therapy within 3 months prior to signing the consent

28. History of pancreatic carcinoma

29. Acute pancreatitis < 180 days before screening

30. History or presence of chronic pancreatitis

31. Presence of concerning thyroid nodule

32. Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) > 6.0 mIU/L or < 0.1 mIU/L before the first study visit

33. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

34. Evidence or history of ascites or spontaneous bacterial peritonitis that require(d) treatment

• Trace ascites identified only by an abdominal imaging without other evidence of clinically significant portal hypertension and esophageal varices is not an exclusion criterion.

35. Evidence or history of hepatic encephalopathy

36. Evidence or history of variceal bleeding

37. Evidence or history of portosplenic vein thrombosis

38. 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.

39. 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).

40. ALT or AST or Alkaline phosphatase >200 U/L

41. Recurrent major hypoglycemia or hypoglycemic unawareness

42. Inability to safely obtain a liver biopsy

43. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study

44. Unable to understand the risks, benefits, and compliance requirements of study

45. Lack capacity to give informed consent

46. Plans to move outside the primary location of study (country) within the next 24 months

47. Known or suspected allergy to semaglutide, tirzepatide, liraglutide, excipients, or related products

48. Previous participation in this trial and got randomized to one of the study groups but did not proceed.

49. Hospitalization due to COVID-19 within 2 months prior to screening.

50. Platelet count <80,000

51. International Normalized Ratio (INR) >1.7

52. Child-Pugh score B or C

53. MELD score ≥15

54. Upper endoscopy showing gastroesophageal varices

55. Upper endoscopy showing more than mild portal hypertensive gastropathy

56. 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.

Note: Negative findings on upper endoscopy and liver duplex ultrasound (done within one year of the first study visit for both tests) are necessary to establish eligibility for the FLAMES.

57. Cross-sectional abdominal imaging (if available historically) indicating presence of large portosystemic collaterals or ascites

• Splenomegaly alone (in the absence of other radiological and laboratory findings) is not considered to be a sign of clinically significant portal hypertension and is not an exclusion criterion.

58. HVPG ≥ 12 mmHg (if available historically or if measured at the time of de novo liver biopsy)

59. Liver biopsy characteristics: