Metformin in Heart Failure Without Diabetes

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 (n=50) 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 assessment, exercise capacity, echocardiography, cardiac PET imaging and blood tests.

Eligibility Criteria:
Inclusion Criteria:

* Age \>18yrs old
* 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 should be implanted, if indicated. Patients with a CRT device should be treated for \> 3 months.
* Reduced ejection fraction defined as LVEF ≤ 35%
* 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(24)
* Non-insulin resistant defined as a fasting insulin resistance index, or HOMA-IR of \<2.7.
* Non-diabetic defined as a HgbA1c \<6.0

Exclusion Criteria:

* Any oral or injectable hypoglycemic therapy (e.g. insulin, sulfonylureas)
* Known allergy to metformin or major side effects to metformin treatment
* Concomitant use of a carbonic anhydrase inhibitor (such as acetazolamide or topirafmate)
* Heart Failure Hospitalizations in the past 3 months (primary diagnosis on admission is heart failure)
* Acute myocardial infarction, unstable angina or revascularization with prior 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 primary cardiac valve disease, specifically severely stenotic or regurgitant mitral or aortic valves
* 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 (\> 110 beats/min)
* Hypertrophic or restrictive cardiomyopathy, infiltrative or storage myocardial disease, active myocarditis, or pericardial disease.
* Planned major surgery within the study period
* 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
* Liver disease with ALT or AST \>3 times upper normal limit (it is possible to repeat this measurement once within a month)
* Advanced lung disease such as COPD
* Significant comorbidity or issue that makes the patient unsuitable for participation as judged by the investigator
* Participation in another study involving long-term medical intervention (participation in device studies is allowed)