Effects of Metformin on Hepatic Venous Pressure Gradient in Patients With Cirrhosis and Portal Hypertension

Prior treatment

• Ongoing treatment with metformin, or discontinued for less than 3 months
• Treatment with statins started or discontinued for less than 3 months
• Treatment with nucleoside/nucleotide analogue for HBV, or direct-acting antiviral treatment for HCV, started for less than 6 months

Other illness

• Known hypersensitivity to the active substance or any of the excipients
• History of lactic acidosis, diabetic acidocetosis, or diabetic precoma
• Ongoing condition that may lead to acute kidney injury or hypoxia: dehydration, severe infection, shock, cardiac decompensation, respiratory failure, or myocardial infarction within the past month
• Known hypersensitivity to all the iodin-containing contrast agents
• Known hypersensitivity to lidocaine for local anesthesia
• Known hypersensitivity to beta-lactam antibiotics if the patient has a history of valve replacement
• Extra-hepatic cancer without remission
• Severe chronic kidney disease defined as estimated glomerular filtration rate \< 30 mL/min/1,73m2 using the MDRD-6 formula
• Complete portal vein thrombosis (main portal trunk, or right branch), or portal cavernoma
• History of TIPS (transjugular intrahepatic portosystemic shunt) / surgical portosystemic derivation / liver transplantation / major hepatectomy

Lab values

• Serum total bilirubin \> 50 µmol/L
• Transaminases \> 5 ULN

Other

• Prothrombin ratio \< 50 %
• Need for at least one paracentesis for ascites fluid evacuation in the last 6 months
• Expected follow-up \< 3 months
• Alcohol consumption \> 14 units/week for women or \> 21 units/week for men, current or abstinent for less than 6 months
• Biliary cirrhosis
• Hepatocellular carcinoma with at least one nodule \> 3 cm in diameter, or more than 3 nodules
• Cholangiocarcinoma
• Ongoing participation in another interventional therapeutic trial
• Pregnant or breastfeeding women
• Patients unable to give consent (under guardianship or curatorship)
• Non-randomisation criteria: HVPG \< 12 mm Hg at the catheterism performed during the first follow-up visit

• \- Age ≥ 18 years
• Written informed consent to participate in the study
• Medical insurance coverage
• For child-bearing aged women, contraception using oestroprogestative, progestative, intrauterine device, or mechanical contraception
• Diagnosis of cirrhosis based on a liver biopsy, or on clinical, biological, endoscopic, and radiological evidence
• Active cause of cirrhosis, or resolution (alcohol cessation, sustained virological response to direct-acting antiviral treatment for HCV, initiation of nucleoside/nucleotide analog treatment for HBV) for at least 6 months
• Child-Pugh A or B
• High likelihood of HVPG ≥ 12 mm Hg based on investigator's judgement, or on the following criteria:
  • Investigator's judgement
  • active cause of cirrhosis and:
  • History of clinical ascites
  • Or history of variceal bleeding
  • Or liver stiffness by VCTE ≥ 35 kPa on carvedilol in the last two years
  • or spleen stiffness by VCTE ≥ 55 kPa on carvedilol in the last two years
  • or liver surface nodularity ≥ 2,9 in the last two years
  • or HVPG \&gt; 16 mm Hg prior to starting NSBB
  • or Laennec 4c cirrhosis on histology
  • or resolution of the cause of cirrhosis for at least 6 months and:
  • history of clinical ascites in the last 6 months
  • or history of variceal bleeding in the last 6 months
  • or liver stiffness by VCTE ≥ 35 kPa on carvedilol in the last 6 months
  • or spleen stiffness by VCTE ≥ 55 kPa on carvedilol in the last 6 months
  • or liver surface nodularity ≥ 2,9 in the last 12 months
  • or Laennec 4c cirrhosis on histology in the last 12 months
• Treatment with carvedilol (≥ 6,25 mg/day) at a stable dose for at least one month
• Absence of hepatocellular carcinoma outside at least one nodule \&gt; 3 cm in diameter, or more than 3 nodules, on ultrasound, CT-scan or MRI performed during the previous 6 months