A Study of Metformin to Improve Cardiac Function After LVAD Implantation

Study on the Effect of Metformin in Improving Cardiac Function After Implantation of Left Ventricular Assist Devices

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Left Ventricular Assist Device
• Intervention / Treatment: Drug: Metformin Hydrochloride; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Ha’erbin, China, 150001
    • Recruiting
    • The First Affiliated Hospital of Harbin Medical University
    • Contact: Xie, Dr.; Phone Number: +8613059008055; Email: baodongxie_doctor@aliyun.com
  • Huai'an, China, 223300
    • Recruiting
    • Huai'an Hospital Affiliated to Yangzhou University
    • Contact: Li, Dr.; Phone Number: +8615996187390; Email: hongskj@163.com
  • Zhengzhou, China, 450000
    • Recruiting
    • Henan Provincial Chest Hospital, Chest Hospital of Zhengzhou University
    • Contact: He, Dr.; Phone Number: +8613838338095; Email: 13838338095@163.com
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Recruiting
      • Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University
      • Contact: Tuo Pan, MD; Phone Number: +8615205160210; Email: pan_tuo@126.com
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Affiliated Hospital of Zhejiang University school of medicine
      • Contact: Pan, Dr.; Phone Number: +8613732255304; Email: pandihao@zju.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin Group; Metformin hydrochloride tablets administered orally with a dose-escalation schedule to reduce gastrointestinal adverse effects and risk of lactic acidosis. The titration schedule is as follows: Weeks 1-2: 250 mg once daily (after dinner); Weeks 3-4: 500 mg once daily (after dinner); Weeks 5-6: 750 mg total daily (500 mg after dinner + 250 mg after breakfast); Weeks 7-8: 1000 mg total daily (500 mg after dinner + 500 mg after breakfast) - target dose; Weeks 9-10: 1250 mg total daily (500 mg after dinner + 750 mg after breakfast) - optional target dose. The maintenance period extends from Week 10 to Week 52, during which patients maintain the target dose or maximum tolerated dose (must be ≥750 mg per day). Dose adjustment or temporary withholding may be considered based on tolerability and renal function (eGFR).	Drug: Metformin Hydrochloride; Metformin hydrochloride tablets, 250 mg and 500 mg, administered orally with a dose-escalation schedule over 10 weeks to achieve target dose, followed by a maintenance period from Week 10 to Week 52. Dose adjustments based on tolerability and renal function.
Placebo Comparator: Placebo Group; Matching placebo tablets, identical in appearance to metformin, administered orally following the same dose-escalation schedule as the metformin group (based on tablet count), from Week 1 through Week 52.	Drug: Placebo; Matching placebo tablets, identical in appearance to metformin, administered orally following the same dose-escalation and maintenance schedule as the active comparator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Full Responder at 12 Months Post-LVAD Implantation	Full Responder is defined as meeting all of the following four criteria at 12 months post-implantation: (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.	12 months post-LVAD implantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Clinical Adverse Events	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. Each event will be reported separately.	Up to 24 months post-LVAD implantation
Partial Responder incidence	Incidence of Partial Responder, defined as meeting the Utah-Inova Partial Responder criteria (improvement in left ventricular ejection fraction [LVEF] from baseline ≥5 percentage points, but absolute LVEF remains <40%).	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Composite fibrotic phenotype incidence	Incidence of composite fibrotic phenotype, defined as soluble ST2 (sST2) >100 ng/mL at both 6 months and 12 months AND absolute global longitudinal strain (GLS) <10% at 12 months.	6 and 12 months post-LVAD implantation
Change in left ventricular ejection fraction (LVEF)	Change from baseline in LVEF (measured in percentage points).	12 months and 24 months post-LVAD implantation
Change in left ventricular end-diastolic diameter (LVEDD)	Change from baseline in LVEDD (measured in millimeters, mm)	12 months and 24 months post-LVAD implantation
Change in absolute global longitudinal strain (GLS)	Change from baseline in absolute GLS (measured in percentage, %).	12 months and 24 months post-LVAD implantation
Change in soluble ST2 (sST2)	Change from baseline in soluble ST2 (sST2) level. Unit of Measure: ng/mL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in B-type natriuretic peptide (BNP)	Change from baseline in B-type natriuretic peptide (BNP) level. Unit of Measure: pg/mL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in triglyceride-glucose (TyG) index	Change from baseline in TyG index, calculated as Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Unit of Measure: Unitless (index value)	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in fasting glucose	Change from baseline in fasting glucose level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in fasting insulin	Change from baseline in fasting insulin level. Unit of Measure: μU/mL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in HOMA-IR index	Change from baseline in homeostatic model assessment for insulin resistance (HOMA-IR) index, calculated as fasting glucose (mmol/L) × fasting insulin (μU/mL) / 22.5. Unit of Measure: Unitless (index value)	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in hemoglobin A1c (HbA1c)	Change from baseline in HbA1c level. Unit of Measure: %	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in total cholesterol	Change from baseline in total cholesterol level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in triglycerides	Change from baseline in triglyceride level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in HDL-C	Change from baseline in high-density lipoprotein cholesterol (HDL-C) level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in LDL-C	Change from baseline in low-density lipoprotein cholesterol (LDL-C) level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in ALT	Change from baseline in alanine aminotransferase (ALT) level. Unit of Measure: U/L	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in AST	Change from baseline in aspartate aminotransferase (AST) level. Unit of Measure: U/L	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in total bilirubin	Change from baseline in total bilirubin level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in serum creatinine	Change from baseline in serum creatinine level. Unit of Measure: mg/dL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in eGFR	Change from baseline in estimated glomerular filtration rate (eGFR). Unit of Measure: mL/min/1.73m²	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in serum lactate	Change from baseline in serum lactate level. Unit of Measure: mmol/L	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in serum vitamin B12	Change from baseline in serum vitamin B12 level. Unit of Measure: pg/mL	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in 6-minute walk distance (6MWD)	Change from baseline in 6-minute walk distance. Unit of Measure: meters (m)	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in peak oxygen consumption (VO₂max)	Change from baseline in peak oxygen consumption measured by cardiopulmonary exercise testing. Unit of Measure: mL/kg/min	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score	Change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. The KCCQ is a 23-item self-administered questionnaire that measures physical function, symptoms (frequency and severity), social function, self-efficacy and knowledge, and quality of life in patients with heart failure. Unit of Measure: Points on a scale. Scale Title: Kansas City Cardiomyopathy Questionnaire Overall Summary Score. Minimum Value: 0. Maximum Value: 100. Higher Score Indicates Better Outcome: Yes	1, 3, 6, 12, 18, and 24 months post-LVAD implantation
Adverse event-related discontinuation rate	Proportion of participants who discontinue the study drug due to adverse events. Unit of Measure: Proportion of participants (%)	From baseline through 12 months (treatment period), plus 30 days follow-up
Incidence of lactic acidosis	Incidence of lactic acidosis, defined as serum lactate >5 mmol/L with arterial pH <7.35. Unit of Measure: Proportion of participants (%)	From baseline through 12 months (treatment period), plus 30 days follow-up
Incidence of acute kidney injury (AKI)	Incidence of acute kidney injury, defined according to KDIGO criteria. Unit of Measure: Proportion of participants (%)	From baseline through 12 months (treatment period), plus 30 days follow-up
Incidence of liver function abnormality	Incidence of liver function abnormality, defined as ALT/AST >3× upper limit of normal or total bilirubin >2× upper limit of normal. Unit of Measure: Proportion of participants (%)	From baseline through 12 months (treatment period), plus 30 days follow-up
Incidence of gastrointestinal adverse events	Incidence of gastrointestinal adverse events, including nausea, vomiting, diarrhea, and other related symptoms. Unit of Measure: Proportion of participants (%)	From baseline through 12 months (treatment period), plus 30 days follow-up
Incidence of vitamin B12 deficiency	Incidence of vitamin B12 deficiency, defined as serum vitamin B12 <200 pg/mL. Unit of Measure: Proportion of participants (%)	From baseline through 12 months (treatment period), plus 30 days follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in G6PD Activity (Exploratory)	Change from baseline in glucose-6-phosphate dehydrogenase (G6PD) activity, measured in units per gram of hemoglobin (U/g Hb) or units per milligram of protein (U/mg protein). Assessed in pre-implantation right ventricular myocardial biopsy (obtained only when clinically indicated for temporary pacemaker lead placement) and in serial peripheral blood mononuclear cell (PBMC) samples collected at 3, 6, and 12 months post-implantation.	Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)
Change in NADPH/NADP⁺ Ratio (Exploratory)	Change from baseline in the NADPH to NADP⁺ ratio, expressed as a unitless ratio (no specific units). Assessed in pre-implantation right ventricular myocardial biopsy (obtained only when clinically indicated for temporary pacemaker lead placement) and in serial peripheral blood mononuclear cell (PBMC) samples collected at 3, 6, and 12 months post-implantation.	Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)
Change in Malondialdehyde (MDA) Level (Exploratory)	Change from baseline in malondialdehyde (MDA) level, a marker of lipid peroxidation and oxidative stress, measured in micromoles per liter (μmol/L) or nanomoles per milligram of protein (nmol/mg protein). Assessed in pre-implantation right ventricular myocardial biopsy (obtained only when clinically indicated for temporary pacemaker lead placement) and in serial peripheral blood mononuclear cell (PBMC) samples collected at 3, 6, and 12 months post-implantation.	Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)
Change in 4-Hydroxynonenal (4-HNE) Level (Exploratory)	Change from baseline in 4-hydroxynonenal (4-HNE) level, a marker of lipid peroxidation and oxidative stress, measured in micromoles per liter (μmol/L) or nanograms per milligram of protein (ng/mg protein). Assessed in pre-implantation right ventricular myocardial biopsy (obtained only when clinically indicated for temporary pacemaker lead placement) and in serial peripheral blood mononuclear cell (PBMC) samples collected at 3, 6, and 12 months post-implantation.	Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)
Change in IRS/Akt Phosphorylation (Exploratory)	Change from baseline in insulin receptor substrate (IRS) and Akt phosphorylation levels, expressed as relative units (phosphorylation level normalized to control, unitless). Assessed in pre-implantation right ventricular myocardial biopsy (obtained only when clinically indicated for temporary pacemaker lead placement) and in serial peripheral blood mononuclear cell (PBMC) samples collected at 3, 6, and 12 months post-implantation.	Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)

Collaborators and Investigators

• Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: May 22, 2026
• First Submitted That Met QC Criteria: June 18, 2026
• First Posted (Actual): June 24, 2026

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Metformin; Randomized Controlled Trial; Cardiac Function; LVAD; Full Responder
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Organic Chemicals; Biguanides; Guanidines; Amidines; Metformin
• Other Study ID Numbers: CZLB506-2020

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