Effects of Metformin on Hepatic Venous Pressure Gradient in Patients With Cirrhosis and Portal Hypertension - A Randomized Placebo-controlled Study
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. 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.
• \- 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 \> 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 \> 3 cm in diameter, or more than 3 nodules, on ultrasound, CT-scan or MRI performed during the previous 6 months