Body-weight Reduction Effect on Portal Hypertension in Compensated Cirrhosis

Obesity and metabolic abnormalities accelerate decompensation in compensated cirrhosis, driven by clinically significant portal hypertension (CSPH, HVPG≥10 mmHg). Lifestyle-induced weight loss can lower portal pressure, but pharmacological options are limited. Mazdutide, a dual GLP-1/glucagon receptor agonist, has proven weight-loss and glycaemic benefits, yet its safety and efficacy in cirrhosis with portal hypertension are unknown. This investigator-initiated, single-arm, open-label, exploratory trial evaluates whether mazdutide can safely reduce portal pressure in overweight patients with compensated cirrhosis and CSPH. The main questions it aims to answer are: Does 16-week mazdutide treatment reduce HVPG (percentage change from baseline)? What adverse events occur, and is the drug tolerated? Participants will: Receive mazdutide SC injection once weekly for 16 weeks, titrated from 2 mg to 4 mg to 6 mg (if tolerated), with dose adjustment for intolerance. Undergo HVPG at baseline and week 16 (primary endpoint). Have FibroScan® (liver/spleen stiffness, CAP) at baseline and weeks 4, 8, 12, 16. Provide blood samples for liver, renal, glucose, lipid, and coagulation tests at each visit. Undergo body composition, handgrip strength, and nutritional assessments to monitor muscle mass. Attend clinic visits every 4 weeks during treatment and one follow-up visit 4 weeks post-treatment. Key eligibility: Adults 18-75 with compensated cirrhosis (viral, MASLD, or alcohol-related), HVPG≥10 mmHg, BMI≥28 or ≥26 with comorbidities, stable weight, and stable carvedilol/propranolol if used. Exclude prior decompensation, HCC, CTP≥B8, eGFR\<60, mazdutide contraindications, active infection, uncontrolled hepatitis, portal vein thrombosis, etc. Endpoints: Primary - % change in HVPG. Secondary - HVPG response (≥10% decrease or \<10 mmHg), decompensation events, treatment discontinuation due to AEs. Exploratory - changes in stiffness, liver fat, metabolic parameters, body composi