Clinical trial NCT02810132: Effects of Metformin Treatment on Myocardial Efficiency in Patients With Heart Failure
Official title: Effects of Metformin Treatment on Myocardial Efficiency in Patients With Heart Failure: A Randomized, Double-blind, Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure, Systolic
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
First posted: 2016-06-22
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

  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)

Primary outcomes:
measure: Changes in LV myocardial efficiency
timeFrame: Baseline and 3 months
Secondary outcomes:
measure: Left ventricular global longitudinal strain during peak exercise
timeFrame: Baseline and 3 months
measure: Myocardial oxygen consumption
timeFrame: Baseline and 3 months
measure: Myocardial perfusion at rest
timeFrame: Baseline and 3 months
measure: LV myocardial function evaluated by LVEF and diastolic function
timeFrame: Baseline and 3 months
measure: LV mass
timeFrame: Baseline and 3 months
measure: 6 minute walking distance
timeFrame: Baseline and 3 months
measure: Changes in body composition
timeFrame: Baseline and 3 months
measure: Maximum oxygen consumption
timeFrame: Baseline and 3 months
measure: Degree of insulin resistance
timeFrame: Baseline and 3 months
measure: Minnesota living with heart failure questionnaire
timeFrame: Baseline and 3 months
measure: NT-proBNP
timeFrame: Baseline and 3 months
Other outcomes:
Locations:
city: Aarhus N
country: Denmark
facility: Aarhus University Hospital, Department of Cardiology, Palle Juul-Jensens Boulevard 99
Study officials:
References:
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.