Effects of Metformin on Hepatic Venous Pressure Gradient in Patients With Cirrhosis and Portal Hypertension (Hyper-Met)

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.

Study Overview

• Status: Recruiting
• Conditions: Cirrhosis; Portal Hypertension Related to Cirrhosis
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: LUCILE MOGA; Phone Number: +33 01 71 11 46 69; Email: lucile.moga@aphp.fr
• Study Contact Backup: Name: PIERRE EMMANUEL RAUTOU; Phone Number: +33 01 40 87 52 83; Email: pierre-emmanuel.rautou@aphp.fr

Study Locations

• France
  • Clichy, France, 92110
    • Recruiting
    • Facility Name: Beaujon hospital
    • Contact: Lucile MOGA, Dre; Phone Number: 00331-71-11-46-69; Email: lucile.moga@aphp.fr
    • Contact: Pierre Emmanuel Rautou, Pr; Phone Number: 00331-71-11-46-69; Email: pierre-emmanuel.rautou@aphp.fr
    • Contact: Lucile MOGA, Dre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: METFORMIN GROUP	Drug: Metformin; one pill of 500 mg per os twice a day for 28 days.
Placebo Comparator: PLACEBO GROUP	Drug: Placebo; one pill per os twice a day for 28 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
effect of metformin versus placebo during 28 days on HVPG, in patients with cirrhosis and a HVPG ≥ 12 mm Hg already treated with carvedilol.	HVPG measures before and after metformin or placebo treatment	after 28 days of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the rate of patients with a clinically significant improvement in HVPG	Change in arterial pressure after treatment : HVPG > or = 12 mm Hg, or at least a 10% reduction from baseline,	after 28 days of treatment
Change in cirrhosis severity MELD score	MELD (Model for End-Stage Liver Disease) score classification (6-40 with high score is worse outcome)	after 28 days of treatment
Change in cirrhosis severity Child-Pugh score	Child-Pugh classification or Child-Turcotte-Pugh classification (5-15 with high score is worse outcome)	after 28 days of treatment
change in systemic haemodynamics	The size (diameter) of a blood vessel.	after 28 days of treatment
the tolerability of metformin in patients with cirrhosis and a HVPG ≥ 12 mm Hg	treatment compliance	after 28 days of treatment
Maximum metformin plasma level	plasma level (at 2h30 of last dose)	after 28 days of treatment
Relative changes in HVPG	HVPG measure	day 28
Change in arterial pressure	HVGP	after 28 days of treatment
the safety of metformin in patients with cirrhosis and a HVPG ≥ 12 mm Hg	complication and adverse event evaluate by CTCAE guideline during treatment	30 days after the beginning of treatment
Change in liver steatosis	Controlled Attenuation Parameter with FibroScan®	after 28 days of treatment
Change in markers of systemic inflammation		after 28 days of treatment.
Change in markers of hepatocyte stress	hepatocyte large extracellular vesicles	after 28 days of treatment
Change in markers of endothelial function		after 28 days of treatment
Change in platelet count		after 28 days of treatment
Change in liver stiffness by VCTE	using FibroScan®	after 28 days of treatment
Change in liver stiffness by 2D-shear wave elastography	using Aixplorer®	after 28 days of treatment
Change in SPLEEN stiffness by VCTE	using FibroScan®	after 28 days of treatment
Change in spleen stiffness by 2D-shear wave elastography	using Aixplorer®	after 28 days of treatment

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Rittig N, Aagaard NK, Villadsen GE, Sandahl TD, Jessen N, Gronbaek H, George J. Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther. 2021 Aug;54(3):320-328. doi: 10.1111/apt.16460. Epub 2021 Jun 24.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2025
• Primary Completion (Estimated): March 30, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: October 31, 2024
• First Submitted That Met QC Criteria: November 12, 2024
• First Posted (Actual): November 13, 2024

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: metformin; portal hypertension; cirrhosis; carvedilol; hepatic venous pressure gradient
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Digestive System Diseases; Liver Diseases; Hypertension; Fibrosis; Liver Cirrhosis; Hypertension, Portal; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: APHP230872

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No