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

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Metformin Hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Giza, Egypt, 12566
    • Agouza Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; 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.	Drug: Metformin Hydrochloride; Metformin 2000 mg/day; Other Names: Glucophage; Cidophage
No Intervention: Standard of Care; Patients in the control arm will continue the SOC medications

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total antioxidant capacity (relative and absolute)	Change Total antioxidant capacity as assessed by colorimetric assay	6 months
Change in Malondialdehyde (MDA)	Change in Malondialdehyde (MDA) as assessed by colorimetric assay	6 months
Chagne in left ventricular mass index	Chagne in left ventricular mass index as assessed by Echocardiography	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chagne in Ejection Fraction	Ejection fraction as assessed by echocardiography	6 months
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	6 months
TAC	Total antioxidant capacity as assessed by colorimetric assay	6 months
MDA	MDA as assessed by colorimetric assay	6 months
Adverse reactions of metformin	Incidence of lactic acidosis	6 months
Change in fasting blood glucose (FBG)	Change in FBG from baseline	6 months

Collaborators and Investigators

• Sponsor: Cairo University
• Investigators: Principal Investigator: Ahmed M Kamel, MSc., Faculty of Pharmacy, Cairo University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2021
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): April 30, 2023

Study Registration Dates

• First Submitted: December 16, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): January 4, 2022

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 17, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Heart failure; Metformin; Non-diabetic; left ventricular mass index
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: CL (2582)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No