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

Effects of Metformin Treatment on Myocardial Efficiency in Patients With Heart Failure: A Randomized, Double-blind, Placebo-controlled Study

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure, Systolic
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus University Hospital, Department of Cardiology, Palle Juul-Jensens Boulevard 99

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Drug: Placebo	Drug: Placebo; See above
Active Comparator: Metformin; Drug: Metformin Target dose: 1000 mg x 2 (if eGFR 30-60 ml/min: 500 mg x 2) Other name: Glucophage XR 500	Drug: Metformin; See above; Other Names: Glucophage XR 500

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Measured by bioelectrical impedance analysis (BIA)	Baseline and 3 months
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

Collaborators and Investigators

• Sponsor: Aarhus University Hospital

Publications and helpful links

General Publications

• Larsen AH, Wiggers H, Dollerup OL, Jespersen NR, Hansson NH, Frokiaer J, Brosen K, Norrelund H, Botker HE, Moller N, Jessen N. Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: a Randomized, Double-Blind, Placebo-Controlled Study. Cardiovasc Drugs Ther. 2021 Jun;35(3):491-503. doi: 10.1007/s10557-020-07050-5. Epub 2020 Aug 8.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2017
• Primary Completion (Actual): February 14, 2018
• Study Completion (Actual): February 14, 2018

Study Registration Dates

• First Submitted: June 8, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimate): June 22, 2016

Study Record Updates

• Last Update Posted (Actual): April 20, 2018
• Last Update Submitted That Met QC Criteria: April 19, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Systolic; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 2015-588

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No