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

Portal hypertension (PHT) is defined by an elevated pressure gradient between the portal vein and the hepatic veins ≥ 5 mm Hg, and is the main vector of complications in cirrhosis. When the hepatic venous pressure gradient (HVPG) is ≥ 10 mm Hg, it is considered as a " clinically significant PHT ": ascites and oesophageal varices (EV) may occur. Above 12 mm Hg, there is a risk of variceal bleeding. Carvedilol, a non-selective beta-blocker (NSBB), is recommended in all the patients with cirrhosis and clinically significant PHT in order to prevent decompensation of cirrhosis. Nevertheless, 40 % of patients are NSBB non-responders, i.e. they do not show a significant decrease in HVPG. In addition, NSBB responders treated for primary prophylaxis have an incidence of variceal bleeding of approximately 10% per year, with a six-week mortality of 20%. Therefore, there is an unmet need for PHT in patients with cirrhosis who do not respond to NSBB, and also for an increase in efficacy in responders. In a randomised pilot study, Rittig et al. observed a mean change in HVPG of -2,9 mm Hg in 16 patients with cirrhosis and HVPG ≥ 12 mm Hg, not treated with NSBB, 90 minutes after ingestion of 1000 mg metformin. The study will be a prospective, national, multicentre, phase II, superiority comparative randomized (1:1) simple-blinded clinical trial with two parallel arms: metformin versus placebo. The main objective is to evaluate the effect of metformin versus placebo during 28 days on HVPG, in patients with cirrhosis and a HVPG ≥ 12 mm Hg already treated with carvedilol. There are several secondary objectives in this research listed below: * evaluate the safety and tolerability of metformin in patients with cirrhosis and a HVPG ≥ 12 mm Hg * evaluate the rate of change in HVPG after 28 days of treatment * evaluate the rate of patients with a clinically significant improvement in HVPG * assess the change in systemic haemodynamics after 28 days of treatment * assess the change in liver steatosis after 28 days of treatment * assess the performance of liver and spleen stiffness by vibration-controlled transient elastography (VCTE) using FibroScan® (Echosens, Paris, France) to estimate the haemodynamic response to the treatment * assess the performance of liver and spleen stiffness by 2D-shear wave elastography using Aixplorer® (SuperSonic Imagine, Aix-en-Provence, France) to estimate the haemodynamic response to the treatment * assess the effect of metformin on systemic inflammation, coagulation, hepatocyte stress, and endothelial function. Subjects randomized in the metformin group or placebo group will receive metformin ou placebo, one pill of 500 mg per os twice a day (one in the morning and one in the evening, during or at the end of the meal) for 28 days.