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Efficacy of Metformin as add-on Therapy in Non-Diabetic Heart Failure Patients

Primary Purpose

Heart Failure

Status

Completed

Phase

Phase 4

Locations

Egypt

Study Type

Interventional

Intervention

Metformin Hydrochloride

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Metformin, Heart failure, Non-diabetic, left ventricular mass index

Eligibility Criteria

18 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Chronic heart failure (>6 months duration)
Stabilized on 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).
Reduced ejection fraction defined as LVEF < 40%
NYHA-class II or III or IV with stable symptoms for at least the past 3 months
Creatinine clearance > 45 ml/min

Exclusion Criteria:

Diabetes mellitus: Diabetes will be diagnosed using the 2018 The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes 15
- FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*
- 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.
- A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*
- In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).
Any oral or injectable hypoglycemic therapy (e.g. insulin, sulfonylureas)
Recent Hospitalizations in the past 3 months
Metformin treatment within the last 3 months
Creatinine clearance below 45 in the prior 6 months as assessed by Cockcroft and Gault equation
Known allergy to metformin or major side effects to metformin treatment
Atrial fibrillation with poorly controlled ventricular rate at rest (> 100 beats/min)
Hypertrophic cardiomyopathy

Sites / Locations

Agouza Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Metformin

Standard of Care

Arm Description

Patients in the metformin group will receive a starting dose of 1000 mg/day. The dose will be titrated as tolerated to a maximum of 2000 mg/. Patients will receive the medications for six year and will be followed up for the duration of the study. Patients will be assessed at baseline, 3 months, and 6 months.

Patients in the control arm will continue the SOC medications

Outcomes

Primary Outcome Measures

Change in total antioxidant capacity (relative and absolute)

Change Total antioxidant capacity as assessed by colorimetric assay

Change in Malondialdehyde (MDA)

Change in Malondialdehyde (MDA) as assessed by colorimetric assay

Chagne in left ventricular mass index

Chagne in left ventricular mass index as assessed by Echocardiography

Secondary Outcome Measures

Chagne in Ejection Fraction

Ejection fraction as assessed by echocardiography

New York Heart Association functional classification (NYHA):

The NYHA classifies patients in one of four possible categories based on the physical activity limitations; the limitations/symptoms are in regards to normal breathing andvarying degrees in shortness of breath and or angina pain

TAC

Total antioxidant capacity as assessed by colorimetric assay

MDA

MDA as assessed by colorimetric assay

Adverse reactions of metformin

Incidence of lactic acidosis

Change in fasting blood glucose (FBG)

Change in FBG from baseline

Full Information

NCT ID

NCT05177588

First Posted

December 16, 2021

Last Updated

July 17, 2023

Sponsor

Cairo University

1. Study Identification

Unique Protocol Identification Number

NCT05177588

Brief Title

Efficacy of Metformin as add-on Therapy in Non-Diabetic Heart Failure Patients

Official Title

Efficacy of Metformin as add-on Therapy in Non-Diabetic Heart Failure Patients

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

July 21, 2021 (Actual)

Primary Completion Date

March 30, 2023 (Actual)

Study Completion Date

April 30, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Cairo University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

There is an increasing interest in the use of metformin in CV diseases and there is an increasing interest in studying its potential new roles in heart failure patients. There were some concerns related to the safety of metformin in such diabetic patients due to the risk of lactic acidosis. However, recent studies showed that metformin was safe or even beneficial in HF patients. We hypothesized that metformin might improve morbidity, mortality, cardiac function, and HR-QoL in non-diabetic patients with HFrEF.

Detailed Description

Metformin is an anti-diabetic drug that is known improve insulin sensitivity and reduce insulin resistance. A published meta-analysis of randomized controlled trials (RCTs) reported a reduction of weight and insulin resistance in metformin users. Animal models also showed that metformin reduces cardiac hypertrophy. Observational studies showed a beneficial effect for metformin in patients with type 2 diabetes mellitus (T2DM) and heart failure. A recent study found that metformin reduced oxidative stress in non-diabetic patients with CAD. Metformin has multiple modes of actions involving both AMP-activated protein kinase (AMPK) dependent and AMPK-independent mechanisms that may be implicated in cardiac hypertrophy. At the systemic level, a review of clinical and experimental data showed that metformin improves endothelial function, protects from oxidative stress and inflammation, as well as the negative effects of angiotensin II. Observational studies also reported cardiovascular benefits in metformin users especially in patients with type 2 diabetes mellitus (T2DM) and heart failure. Metformin has also been shown to exert a cardio protective effect and it has been shown to reduce oxidative stress which is a common finding in heart failure patients. For these reasons, there is an increasing interest in the use of metformin in CV diseases and there is an increasing interest in studying its potential new roles in this aspect. We hypothesized that metformin might improve morbidity, mortality, cardiac function, and HR-QoL in non-diabetic patients with HFrEF.

6. Conditions and Keywords

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

Heart Failure

Keywords

Metformin, Heart failure, Non-diabetic, left ventricular mass index

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

This is a prospective, interventional, randomized controlled, open label study. The study sample will include heart failure patients with pre-diabetes

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

70 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Metformin

Arm Type

Experimental

Arm Description

Arm Title

Standard of Care

Arm Type

No Intervention

Arm Description

Patients in the control arm will continue the SOC medications

Intervention Type

Drug

Intervention Name(s)

Metformin Hydrochloride

Other Intervention Name(s)

Glucophage, Cidophage

Intervention Description

Metformin 2000 mg/day

Primary Outcome Measure Information:

Title

Change in total antioxidant capacity (relative and absolute)

Description

Change Total antioxidant capacity as assessed by colorimetric assay

Time Frame

6 months

Title

Change in Malondialdehyde (MDA)

Description

Change in Malondialdehyde (MDA) as assessed by colorimetric assay

Time Frame

6 months

Title

Chagne in left ventricular mass index

Description

Chagne in left ventricular mass index as assessed by Echocardiography

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Chagne in Ejection Fraction

Description

Ejection fraction as assessed by echocardiography

Time Frame

6 months

Title

New York Heart Association functional classification (NYHA):

Description

Time Frame

6 months

Title

TAC

Description

Total antioxidant capacity as assessed by colorimetric assay

Time Frame

6 months

Title

MDA

Description

MDA as assessed by colorimetric assay

Time Frame

6 months

Title

Adverse reactions of metformin

Description

Incidence of lactic acidosis

Time Frame

6 months

Title

Change in fasting blood glucose (FBG)

Description

Change in FBG from baseline

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

79 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Chronic heart failure (>6 months duration) Stabilized on recommended or maximally tolerated dose of ACE-I/ARB or ARNI (unless contraindicated) and beta-blocker (unless contraindicated). If indicated, an aldosterone receptor antagonist should be given (unless contraindicated). Reduced ejection fraction defined as LVEF < 45% NYHA-class II or III or IV with stable symptoms for at least the past 3 months Creatinine clearance > 45 ml/min Exclusion Criteria: Diabetes mellitus: Diabetes will be diagnosed using the 2018 The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes 15 FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water. A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L). Any oral or injectable hypoglycemic therapy (e.g. insulin, sulfonylureas) Recent Hospitalizations in the past 3 months Metformin treatment within the last 3 months Creatinine clearance below 45 in the prior 6 months as assessed by Cockcroft and Gault equation Known allergy to metformin or major side effects to metformin treatment Atrial fibrillation with poorly controlled ventricular rate at rest (> 100 beats/min) Hypertrophic cardiomyopathy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ahmed M Kamel, MSc.

Organizational Affiliation

Faculty of Pharmacy, Cairo University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Agouza Hospital

City

Giza

ZIP/Postal Code

12566

Country

Egypt

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

31863557

Citation

Larsen AH, Jessen N, Norrelund H, Tolbod LP, Harms HJ, Feddersen S, Nielsen F, Brosen K, Hansson NH, Frokiaer J, Poulsen SH, Sorensen J, Wiggers H. A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes. Eur J Heart Fail. 2020 Sep;22(9):1628-1637. doi: 10.1002/ejhf.1656. Epub 2019 Dec 21.

Results Reference

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PubMed Identifier

30993313

Citation

Mohan M, Al-Talabany S, McKinnie A, Mordi IR, Singh JSS, Gandy SJ, Baig F, Hussain MS, Bhalraam U, Khan F, Choy AM, Matthew S, Houston JG, Struthers AD, George J, Lang CC. A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial. Eur Heart J. 2019 Nov 1;40(41):3409-3417. doi: 10.1093/eurheartj/ehz203.

Results Reference

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Efficacy of Metformin as add-on Therapy in Non-Diabetic Heart Failure Patients

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