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

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 virologicalresponse to direct-acting antiviral treatment for HCV, initiation ofnucleoside/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 thefollowing 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 indiameter, or more than 3 nodules, on ultrasound, CT-scan or MRI performed during theprevious 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 myocardialinfarction 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 ofvalve replacement

• Alcohol consumption > 14 units/week for women or > 21 units/week for men, current orabstinent for less than 6 months

• Biliary cirrhosis

• Hepatocellular carcinoma with at least one nodule > 3 cm in diameter, or more than 3nodules

• Cholangiocarcinoma

• Extra-hepatic cancer without remission

• Severe chronic kidney disease defined as estimated glomerular filtration rate < 30mL/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 antiviraltreatment for HCV, started for less than 6 months

• Complete portal vein thrombosis (main portal trunk, or right branch), or portalcavernoma

• History of TIPS (transjugular intrahepatic portosystemic shunt) / surgicalportosystemic 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 thefirst follow-up visit