Metformin in Heart Failure Without Diabetes

Study Overview
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Brief Summary
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Columbia University Medical Center is conducting a pilot clinical research study that will assess the use of the medication metformin for heart failure in patients who are not diabetic and have no evidence of insulin resistance. Patients will received either the study drug metformin or placebo for 4 months. During the study, the patients will undergo extensive testing that will include symptom assesment, exercise capacity, echocardiography, cardiac PET imaging and blood tests.

Official Title
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Metformin in Heart Failure Without Diabetes

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Metformin hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic heart failure (defined as >6 months duration) uptitrated to recommended or maximally tolerated dose of ACE-I/ARB (unless contraindicated) and beta-blocker (unless contraindicated). If indicated, an aldosterone receptor antagonist should be given (unless contraindicated). An ICD and/or CRT-D should be implanted, if indicated. Patients with a CRT device should be treated for > 3 months. Reduced ejection fraction defined as LVEF < 40% NYHA-class II or III with stable symptoms for at least the past 3 months Renal Function by eGFR > 45 ml/min (MDRD equation) in accordance with FDA guidance on metformin use in CKD Ability to understand the written patient information and to give informed consent Negative urine-HCG for women of childbearing potential Exclusion Criteria: Patients with diabetes or insulin resistant, defined as 1 or more of the following criteria: HbA1c >6.0% within the last 12 months prior to enrollment Impaired fasting insulin resistance index (HOMA-IR) >2.7 Any oral or injectable hypoglycemic therapy (e.g. insulin, sulfonylureas) Recent Hospitalizations in the past 3 months Metformin treatment within the last 3 months eGFR below 45 in the prior 6 months Known allergy to metformin or major side effects to metformin treatment Acute myocardial infarction, unstable angina or revascularization < 3 months at the time of randomization Planned coronary revascularization, heart surgery, CRT implantation or other intervention during the study period that would potentially affect the function of the heart Significant, uncorrected cardiac valve disease Cardiac arrest or life threatening ventricular arrhythmias within the last 3 months (unless treated with an ICD) Atrial fibrillation with poorly controlled ventricular rate at rest (> 100 beats/min) Hypertrophic or restrictive cardiomyopathy, infiltrative or storage myocardial disease, active myocarditis, or pericardial disease. Planned major surgery Female patients who are pregnant, nursing, or of childbearing potential while not practicing effective chemical contraceptive methods (i.e. oral, implanted, injectable, or transdermal contraceptive hormones; intrauterine device) Current abuse of alcohol or drugs Life-expectancy of less than 1 year due to co-existing morbid illness Stroke within the last 6 months Liver disease with P-ALAT >3 times upper normal limit (it is possible to repeat this measurement once within a month) Significant comorbidity or issue that makes the patient unsuitable for participation as judged by the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin for 6 months | Drug: Metformin hydrochloride<br>* Metformin starting at 500mg twice a day and increasing to 1000mg twice a day for a total of 6 months<br>|
| Placebo Comparator: Placebo<br>Matched placebo for 6 months | Drug: Placebo<br>* Similar dosing regime as active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Minute Ventilation to Carbon Dioxide Production (VE/VCO2) Slope |  | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Dyspnea Assesment Score | 100mm Visual Analog Scale. 100mm line scale ranging from 0 (worse imaginable breathing) to 100 (best imaginable breathing) | Baseline and 6 months | 
| Minnesota Health Living with Heart Failure Questionnaire | Score | Baseline and 6 months | 
| Left Ventricular Function Evaluated by Ejection Fraction and Diastolic Function on Echocardiography |  | Baseline and 6 months | 
| Global Longitudinal Strain and Strain Rate Measured on Echocardiography |  | Baseline and 6 months | 
| B Type Natriuretic Peptide (BNP) level |  | Baseline and 6 months | 
| Body Weight | kg | Baseline and 6 months | 
| Peak Myocardial Oxygen Consumption (VO2) |  | Baseline and 6 months | 
| Quantitative 18F-FDG Activity in 9 Myocardial Segments | Glucose Metabolism | Baseline and 6 months | 
| Quantitative N13-NH3 Activity in 9 Myocardial Segments | Perfusion | Baseline and 6 months | 
| Heart Failure Hospitalizations | number | Over 6 months |