Effects of Metformin Treatment on Myocardial Efficiency in Patients With Heart Failure

Background: Heart failure (HF) is a common disease and diabetes/insulin resistance are present in approximately 50 % of HF patients. Metformin is the most commonly prescribed oral anti-diabetic drug, and registry and experimental studies show beneficial effects of metformin in HF, but randomized trials are needed.

Objectives: To investigate if treatment with metformin in patients with HF has beneficial effects on myocardial efficiency,

Design: A randomized, double-blind, placebo-controlled, single-center design. 36 patients with systolic heart failure will be randomized to either metformin (N = 18) or placebo (N= 18) for 3 months.

Methods: Patients will undergo echocardiography at rest and during exercise along with [11C]-acetate PET.

Primary outcome parameter is changes in myocardial external efficiency from visit 1 to 3 months of therapy.

Inclusion criteria

• Patients with chronic heart failure 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.
• LVEF < 45%
• NYHA-class II, III or IV
• Relatively preserved renal function (eGFR > 30 ml/min)
• Ability to understand the written patient information and to give informed consent
• Negative urine-HCG for women of childbearing potential
• Patients must have insulin resistance, defined as 1 or more of the following criteria:

• HbA1c 5.5 - 6.4% (37 - 47 mmol/mol) within the last 12 months prior to enrolment
• Impaired fasting glucose (IFG): Fasting P-glucose 5.6 - 6.9 mmol/l within 12 months prior to enrolment (patient in stable condition)
• Impaired glucose tolerance (IGT) if OGTT has been performed at any time prior to enrolment: Fasting P-glucose < 7.0 mmol/l and 2 hour P-glucose 7.8 -11.0 mmol/l

Exclusion criteria

• Metformin treatment within the last 3 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
• 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)
• Age < 18 years
• Current abuse of alcohol or drugs
• Cancer, with a life-expectancy of less than 2 years
• 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
• Participation in another study involving long-term medical intervention (participation in device studies is allowed)