This study investigates whether metformin, compared with placebo, improves cardiac function in patients after Left Ventricular Assist Device (LVAD) implantation. Metformin is a widely used oral medication for type 2 diabetes, but emerging evidence suggests it may have beneficial effects on cardiac metabolism and function independent of its glucose-lowering effects. This is a prospective, multicenter, randomized, double-blind, placebo-controlled trial. A total of 108patients undergoing LVAD implantation will be enrolled from 5 centers in China. Eligible participants will be randomly assigned in a 1:1 ratio to receive either metformin or placebo for 12 months.

The primary outcome is the incidence of Full Responder at 12 months post-implantation. A Full Responder is defined as meeting all of the following four criteria: (1) left ventricular ejection fraction (LVEF) ≥40% and left ventricular end-diastolic diameter (LVEDD) ≤6.0 cm (Utah-Inova Responder criteria); (2) soluble ST2 (sST2) ≤100 ng/mL at both 6 months and 12 months post-implantation; (3) absolute value of left ventricular global longitudinal strain (GLS) ≥12% at 12 months post-implantation.

Secondary outcomes include clinical events, cardiac function status, blood biomarker results, global functional status and quality of life, medication safety, and exploratory measures. Clinical events assessed up to 24 months post-implantation include: heart failure rehospitalization rate, all-cause mortality, LVAD explantation rate, cardiovascular mortality, major bleeding, cardiac structural damage, thromboembolic events, systemic inflammatory dissemination, sepsis, and other serious adverse events.

Cardiac function status is evaluated by echocardiographic parameters (LVEF, LVEDD, GLS) and hemodynamic measures. Blood biomarkers include sST2, NT-proBNP, cardiac troponin, and inflammatory cytokines. Global functional status and quality of life are measured using the 6-minute walk test (6MWT), peak oxygen consumption (VO₂max), and the Kansas City Cardiomyopathy Questionnaire (KCCQ). Safety outcomes include the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Exploratory outcomes include pre-implantation right ventricular myocardial biopsy (obtained only when clinically indicated for temporary pacemaker lead placement) to assess insulin receptor substrate (IRS)/Akt phosphorylation, G6PD activity, NADPH/NADP⁺ ratio, and oxidative stress markers (malondialdehyde, 4-hydroxynonenal).

The study aims to provide evidence on whether adjunctive metformin therapy can improve post-LVAD cardiac outcomes and reduce adverse clinical events.

Inclusion Criteria:

• Age 18-75 years
• Receiving continuous-flow LVADs, such as HeartMate 3, HVAD, Core-Heart 6, Brio-Heart
• Presence of insulin resistance
• HbA1c ≤ 6.5%

Exclusion Criteria:

• Diagnosed type 1 diabetes mellitus, or type 2 diabetes mellitus with HbA1c > 6.5% (patients with prior type 2 diabetes who are currently off therapy and have HbA1c ≤ 6.5% may be enrolled; such patients may still have insulin resistance but have achieved glycemic control)
• History of diagnosed diabetic ketoacidosis or hyperosmolar hyperglycemic state
• Currently using any glucose-lowering medications (including insulin, oral hypoglycemic agents, GLP-1 receptor agonists, SGLT2 inhibitors, etc.)
• History of diagnosed polycystic ovary syndrome (PCOS) and currently undergoing treatment
• Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m² (CKD-EPI equation)
• History of acute kidney injury (KDIGO criteria) with incomplete renal recovery
• Receiving any form of renal replacement therapy (hemodialysis, peritoneal dialysis)
• Post-kidney transplantation or awaiting kidney transplantation
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3× the upper limit of normal, total bilirubin > 2× upper limit of normal, or Child-Pugh class B or C cirrhosis
• Active viral hepatitis
• History of alcoholic liver disease or drug-induced liver injury currently in the active phase
• Concurrent right ventricular assist device (RVAD) or total artificial heart implantation
• LVAD-related complications requiring surgical intervention within 30 days postoperatively, including but not limited to: pump thrombosis requiring LVAD exchange or thrombolysis, driveline infection requiring debridement or replacement, hemorrhagic complications requiring re-sternotomy, device malfunction requiring urgent intervention
• Acute kidney injury requiring ongoing renal replacement therapy (CRRT) within 30 days postoperatively
• Preoperative severe right heart failure (on echocardiography: right ventricular fractional area change < 35%, or tricuspid annular plane systolic excursion < 14 mm; or right heart catheterization showing central venous pressure > 15 mmHg and cardiac index < 2.0 L/min/m²)
• Preoperative severe pulmonary arterial hypertension (mean pulmonary arterial pressure ≥ 40 mmHg and pulmonary vascular resistance ≥ 4 Wood units)
• Within 30 days postoperatively, occurrence of severe low cardiac output syndrome requiring extracorporeal membrane oxygenation (ECMO) or intra-aortic balloon pump (IABP) support
• Significant prosthetic valve dysfunction or severe prosthetic valve infectious endocarditis
• Severe unrepaired valvular disease
• Active systemic infection or sepsis requiring ongoing intravenous antibiotics or antifungal therapy
• Active infectious endocarditis (modified Duke criteria) or high clinical suspicion
• Human immunodeficiency virus (HIV) infection with CD4 count < 200/μL or not on regular antiretroviral therapy
• Active tuberculosis or non-tuberculous mycobacterial infection
• Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection
• Known active inflammatory diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease) currently requiring immunosuppressive therapy
• Platelet count < 50 × 10⁹/L, hemoglobin < 80 g/L, international normalized ratio (INR) > 3.0 and not reversible (unless on warfarin with INR within the target range)
• Known bleeding disorders (e.g., hemophilia, von Willebrand disease, acquired von Willebrand syndrome)
• Malignancy diagnosed within the past 5 years (except for cured thyroid cancer, breast cancer, lung cancer, cervical cancer, etc.) and currently receiving chemotherapy, radiotherapy, or targeted therapy
• Prior recipients of heart transplantation or other organ transplants
• Patients awaiting heart transplantation with an anticipated waiting time of less than 3 months
• Pregnant or lactating women
• Reproductive-age women who are capable of conceiving but refuse to use effective contraception during the study period (including surgical sterilization, intrauterine device, oral contraceptives, condoms, etc.)
• Women planning pregnancy during the study
• Known allergy to metformin or any drug excipient
• Known history of lactic acidosis
• Currently using medications that may significantly increase the risk of lactic acidosis, including but not limited to: carbonic anhydrase inhibitors (topiramate, acetazolamide), antiretroviral drugs (especially nucleoside reverse transcriptase inhibitors), certain chemotherapeutic agents (cisplatin)
• Currently using medications that may affect glycemic control or insulin sensitivity and that cannot be stopped or substituted during the study, including but not limited to: systemic glucocorticoids (prednisone-equivalent dose > 10 mg/day for > 2 weeks), high-dose thiazide diuretics (hydrochlorothiazide > 50 mg/day), atypical antipsychotics (olanzapine, clozapine, etc.), immunosuppressants (tacrolimus, cyclosporine, etc.)
• Unable to complete 12-month follow-up
• Known psychiatric disorders or cognitive impairment that may affect informed consent validity or study compliance
• History of drug or alcohol abuse (within the past year)
• Concurrent participation in another clinical trial
• Any other circumstance, as determined by the investigator, that would render the subject unsuitable for enrollment (including but not limited to social, psychological, or geographic factors)

Double-blind, placebo-controlled