Metformin in Heart Failure Without Diabetes (Met-HeFT)

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:

  1. HbA1c >6.0% within the last 12 months prior to enrollment
  2. 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