A Study of Metformin to Improve Cardiac Function After LVAD Implantation

Phase 2RecruitingNCT07666698

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School108 enrolled

Overview

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 Type

INTERVENTIONAL

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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)

Locations (5)

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

Nanjing, Jiangsu, China

RECRUITING

The First Affiliated Hospital of Zhejiang University School of Medicine

Hangzhou, Zhejiang, China

RECRUITING

The First Affiliated Hospital of Harbin Medical University

Ha’erbin, China

RECRUITING

Huai'an Hospital Affiliated to Yangzhou University

Huai'an, China

RECRUITING

Henan Provincial Chest Hospital, Chest Hospital of Zhengzhou University

Zhengzhou, China

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: 12 months post-LVAD implantation

Secondary Outcomes

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.

Time frame: 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%).

Time frame: 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.

Time frame: 6 and 12 months post-LVAD implantation

Change in left ventricular ejection fraction (LVEF)

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

Time frame: 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)

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

Change in absolute global longitudinal strain (GLS)

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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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: %

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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 (%)

Time frame: 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 (%)

Time frame: 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 (%)

Time frame: 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 (%)

Time frame: 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 (%)

Time frame: 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 (%)

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

A Study of Metformin to Improve Cardiac Function After LVAD Implantation

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes