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NCT Number: NCT07666698

A Study of Metformin to Improve Cardiac Function After LVAD Implantation

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.

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Key information

Conditions

Heart Failure Cardiovascular Diseases Heart Diseases Left Ventricular Assist Device

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu, China

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Metformin Hydrochloride

Drug

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

Drug

Matching placebo tablets, identical in appearance to metformin, administered orally following the same dose-escalation and maintenance schedule as the active comparator.

Primary outcomes

  1. Incidence of Full Responder at 12 Months Post-LVAD Implantation

    Time frame: 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.

Secondary outcomes

  1. Composite of Clinical Adverse Events

    Time frame: Up to 24 months post-LVAD implantation

    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.

  2. Partial Responder incidence

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    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%).

  3. Composite fibrotic phenotype incidence

    Time frame: 6 and 12 months post-LVAD implantation

    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.

  4. Change in left ventricular ejection fraction (LVEF)

    Time frame: 12 months and 24 months post-LVAD implantation

    Change from baseline in LVEF (measured in percentage points).

  5. Change in left ventricular end-diastolic diameter (LVEDD)

    Time frame: 12 months and 24 months post-LVAD implantation

    Change from baseline in LVEDD (measured in millimeters, mm)

  6. Change in absolute global longitudinal strain (GLS)

    Time frame: 12 months and 24 months post-LVAD implantation

    Change from baseline in absolute GLS (measured in percentage, %).

  7. Change in soluble ST2 (sST2)

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in soluble ST2 (sST2) level. Unit of Measure: ng/mL

  8. Change in B-type natriuretic peptide (BNP)

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in B-type natriuretic peptide (BNP) level. Unit of Measure: pg/mL

  9. Change in triglyceride-glucose (TyG) index

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in TyG index, calculated as Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Unit of Measure: Unitless (index value)

  10. Change in fasting glucose

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in fasting glucose level. Unit of Measure: mg/dL

  11. Change in fasting insulin

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in fasting insulin level. Unit of Measure: μU/mL

  12. Change in HOMA-IR index

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    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)

  13. Change in hemoglobin A1c (HbA1c)

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in HbA1c level. Unit of Measure: %

  14. Change in total cholesterol

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in total cholesterol level. Unit of Measure: mg/dL

  15. Change in triglycerides

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in triglyceride level. Unit of Measure: mg/dL

  16. Change in HDL-C

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in high-density lipoprotein cholesterol (HDL-C) level. Unit of Measure: mg/dL

  17. Change in LDL-C

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in low-density lipoprotein cholesterol (LDL-C) level. Unit of Measure: mg/dL

  18. Change in ALT

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in alanine aminotransferase (ALT) level. Unit of Measure: U/L

  19. Change in AST

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in aspartate aminotransferase (AST) level. Unit of Measure: U/L

  20. Change in total bilirubin

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in total bilirubin level. Unit of Measure: mg/dL

  21. Change in serum creatinine

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in serum creatinine level. Unit of Measure: mg/dL

  22. Change in eGFR

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in estimated glomerular filtration rate (eGFR). Unit of Measure: mL/min/1.73m²

  23. Change in serum lactate

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in serum lactate level. Unit of Measure: mmol/L

  24. Change in serum vitamin B12

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in serum vitamin B12 level. Unit of Measure: pg/mL

  25. Change in 6-minute walk distance (6MWD)

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in 6-minute walk distance. Unit of Measure: meters (m)

  26. Change in peak oxygen consumption (VO₂max)

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    Change from baseline in peak oxygen consumption measured by cardiopulmonary exercise testing. Unit of Measure: mL/kg/min

  27. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score

    Time frame: 1, 3, 6, 12, 18, and 24 months post-LVAD implantation

    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

  28. Adverse event-related discontinuation rate

    Time frame: From baseline through 12 months (treatment period), plus 30 days follow-up

    Proportion of participants who discontinue the study drug due to adverse events. Unit of Measure: Proportion of participants (%)

  29. Incidence of lactic acidosis

    Time frame: From baseline through 12 months (treatment period), plus 30 days follow-up

    Incidence of lactic acidosis, defined as serum lactate >5 mmol/L with arterial pH <7.35. Unit of Measure: Proportion of participants (%)

  30. Incidence of acute kidney injury (AKI)

    Time frame: From baseline through 12 months (treatment period), plus 30 days follow-up

    Incidence of acute kidney injury, defined according to KDIGO criteria. Unit of Measure: Proportion of participants (%)

  31. Incidence of liver function abnormality

    Time frame: From baseline through 12 months (treatment period), plus 30 days follow-up

    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 (%)

  32. Incidence of gastrointestinal adverse events

    Time frame: From baseline through 12 months (treatment period), plus 30 days follow-up

    Incidence of gastrointestinal adverse events, including nausea, vomiting, diarrhea, and other related symptoms. Unit of Measure: Proportion of participants (%)

  33. Incidence of vitamin B12 deficiency

    Time frame: From baseline through 12 months (treatment period), plus 30 days follow-up

    Incidence of vitamin B12 deficiency, defined as serum vitamin B12 <200 pg/mL. Unit of Measure: Proportion of participants (%)

Other outcomes

  1. Change in G6PD Activity (Exploratory)

    Time frame: Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)

    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.

  2. Change in NADPH/NADP⁺ Ratio (Exploratory)

    Time frame: Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)

    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.

  3. Change in Malondialdehyde (MDA) Level (Exploratory)

    Time frame: Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)

    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.

  4. Change in 4-Hydroxynonenal (4-HNE) Level (Exploratory)

    Time frame: Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)

    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.

  5. Change in IRS/Akt Phosphorylation (Exploratory)

    Time frame: Baseline (pre-implantation biopsy) and 3, 6, 12 months post-implantation (PBMCs)

    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.

Sponsors and collaborators

Lead sponsor

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Other

Registry information

Official study title

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

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Jun 24, 2026
Registry last updated
Sep 2, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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