Effects of Metformin on Portal Hypertension in Cirrhosis Patients

Inclusion Criteria:

* \- 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:

  1. Investigator's judgement
  2. 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 \> 16 mm Hg prior to starting NSBB
     * or Laennec 4c cirrhosis on histology
  3. 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 \> 3 cm in diameter, or more than 3 nodules, on ultrasound, CT-scan or MRI performed during the previous 6 months

Exclusion Criteria:

* Serum total bilirubin \> 50 µmol/L
* Prothrombin ratio \< 50 %
* Transaminases \> 5 ULN
* Need for at least one paracentesis for ascites fluid evacuation in the last 6 months
* Expected follow-up \< 3 months
* 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
* 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
* 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
* 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
* 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
* 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