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

Phase 2

Completed

Brief Summary: The study evaluates the effects of metformin treatment on myocardial efficiency in heart failure patients. 36 patients will be randomized to three months of metformin or placebo treatment in addition to their regular therapy.

Hypothesis: Treatment with metformin in patients with heart failure has direct or indirect beneficial effects on left ventricular myocardial oxidative metabolism, myocardial efficiency and contractile function.

Detailed Description: 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.

Recruitment & Eligibility

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:
1. HbA1c 5.5 - 6.4% (37 - 47 mmol/mol) within the last 12 months prior to enrolment
2. Impaired fasting glucose (IFG): Fasting P-glucose 5.6 - 6.9 mmol/l within 12 months prior to enrolment (patient in stable condition)
3. 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)

Arm && Interventions

Group	Intervention	Description
Metformin	Metformin	Drug: Metformin Target dose: 1000 mg x 2 (if eGFR 30-60 ml/min: 500 mg x 2) Other name: Glucophage XR 500
Placebo	Placebo	Drug: Placebo

Primary Outcome Measures

Name	Time	Method
Changes in LV myocardial efficiency	Baseline and 3 months	LV myocardial efficiency is the ratio between stroke work and myocardial oxygen consumption, which are measured with echocardiography and \[11C\]-acetate PET.

Secondary Outcome Measures

Name	Time	Method
Left ventricular global longitudinal strain during peak exercise	Baseline and 3 months
Myocardial oxygen consumption	Baseline and 3 months
Myocardial perfusion at rest	Baseline and 3 months
LV myocardial function evaluated by LVEF and diastolic function	Baseline and 3 months
LV mass	Baseline and 3 months
6 minute walking distance	Baseline and 3 months
Changes in body composition	Baseline and 3 months	Measured by bioelectrical impedance analysis (BIA)
Maximum oxygen consumption	Baseline and 3 months
Degree of insulin resistance	Baseline and 3 months
Minnesota living with heart failure questionnaire	Baseline and 3 months
NT-proBNP	Baseline and 3 months

Locations (1): Aarhus University Hospital, Department of Cardiology, Palle Juul-Jensens Boulevard 99
🇩🇰
Aarhus N, Denmark