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.
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%
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
Parallel
Metformin Hydrochloride
DrugMetformin 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
DrugMatching placebo tablets, identical in appearance to metformin, administered orally following the same dose-escalation and maintenance schedule as the active comparator.
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.
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.
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%).
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.
Change in left ventricular ejection fraction (LVEF)
Change from baseline in LVEF (measured in percentage points).
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.
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.
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.
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.
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