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

Primary Purpose

Heart Failure, Systolic

Status

Completed

Phase

Phase 2

Locations

Denmark

Study Type

Interventional

Intervention

Metformin

Placebo

About this trial

This is an interventional treatment trial for Heart Failure, Systolic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Aarhus University Hospital, Department of Cardiology, Palle Juul-Jensens Boulevard 99

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Metformin

Placebo

Arm Description

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

Drug: Placebo

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Left ventricular global longitudinal strain during peak exercise

Myocardial oxygen consumption

Myocardial perfusion at rest

LV myocardial function evaluated by LVEF and diastolic function

LV mass

6 minute walking distance

Changes in body composition

Measured by bioelectrical impedance analysis (BIA)

Maximum oxygen consumption

Degree of insulin resistance

Minnesota living with heart failure questionnaire

NT-proBNP

Full Information

NCT ID

NCT02810132

First Posted

June 8, 2016

Last Updated

April 19, 2018

Sponsor

Aarhus University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02810132

Brief Title

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

Acronym

METRONOME

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Completed

Study Start Date

January 20, 2017 (Actual)

Primary Completion Date

February 14, 2018 (Actual)

Study Completion Date

February 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Aarhus University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure, Systolic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Metformin

Arm Type

Active Comparator

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Drug: Placebo

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Glucophage XR 500

Intervention Description

See above

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

See above

Primary Outcome Measure Information:

Title

Changes in LV myocardial efficiency

Description

LV myocardial efficiency is the ratio between stroke work and myocardial oxygen consumption, which are measured with echocardiography and [11C]-acetate PET.

Time Frame

Baseline and 3 months

Secondary Outcome Measure Information:

Title

Left ventricular global longitudinal strain during peak exercise

Time Frame

Baseline and 3 months

Title

Myocardial oxygen consumption

Time Frame

Baseline and 3 months

Title

Myocardial perfusion at rest

Time Frame

Baseline and 3 months

Title

LV myocardial function evaluated by LVEF and diastolic function

Time Frame

Baseline and 3 months

Title

LV mass

Time Frame

Baseline and 3 months

Title

6 minute walking distance

Time Frame

Baseline and 3 months

Title

Changes in body composition

Description

Measured by bioelectrical impedance analysis (BIA)

Time Frame

Baseline and 3 months

Title

Maximum oxygen consumption

Time Frame

Baseline and 3 months

Title

Degree of insulin resistance

Time Frame

Baseline and 3 months

Title

Minnesota living with heart failure questionnaire

Time Frame

Baseline and 3 months

Title

NT-proBNP

Time Frame

Baseline and 3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Facility Information:

Facility Name

Aarhus University Hospital, Department of Cardiology, Palle Juul-Jensens Boulevard 99

City

Aarhus N

ZIP/Postal Code

8200

Country

Denmark

12. IPD Sharing Statement

Citations:

PubMed Identifier

32770520

Citation

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.

Results Reference

derived

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

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