The Effect of Addition of Metformin In Obese Non- Diabetic Patients With Heart Failure With Preserved Ejection Fraction

October 8, 2023 updated by: Sara ElAdawy
Diabetes mellitus people have a higher incidence of cardiovascular disease, and the results of cardiovascular events are worse. Heart failure and diabetes both have a worse prognosis, with a 1.5-2 times increased risk of death. Data from the literature have shown that MET lowers mortality by 14-35% in this patient population, which represents one-third of all HF patients with no increases in lactic acidosis incidence.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Heart failure (HF) with preserved ejection fraction (HFpEF) is a distinct phenotype hallmarked by clinical signs and symptoms of HF coupled with a normal ejection faction (EF ≥ 50%) and evidence of increased left ventricular (LV) pressures and impaired LV filling on echocardiography. HFpEF is highly prevalent, accounting for up to 50% of all patients with HF, and is associated with significant morbidity and mortality. HFpEF is a heterogenous disorder, contributed to by comorbidities that include hypertension, diabetes, obesity, coronary artery disease (CAD), chronic kidney disease (CKD), and specific causes such as cardiac amyloidosis. These chronic conditions complicate the management of HF and have a significant impact on its prognosis. How to generate specific recommendations addressing many of these conditions in the setting of HF is challenging given the current state of the evidence.

Obesity is a growing global concern, and is a common finding in the progression of HFpEF. According to the World Health Organization (WHO), percentage of adult population that is obese in Egypt is 32% which makes it ranks 18th with the highest prevalence of obesity worldwide. Very few studies have been published about the burden of diseases in Egypt in general, and the burden of obesity is even more complex as the impact of obesity is a result of its comorbidities rather than a direct effect. Several studies have provided evidence for the distinct obesity related HFpEF phenotype, and its unique pathophysiology based on the obesity criteria for the European and American population with a body mass index (BMI) greater than 30 kg/m2. Obesity is a commonly occurring comorbidity in patients with HFpEF, and has many deleterious effects on the cardiovascular system, mediated by changes in volume overload, cardiac load, energy substrate utilization, tissue metabolism, and systemic inflammation. However, based on latest heart failure guidelines, evidence gaps and future research directions are needed to assess efficacy and safety of weight loss management and treatment strategies in patients with HF and obesity.

Metformin is a common anti-diabetic drug with both systemic and cardioprotective benefits in addition to its hypoglycaemic effect. At the cellular level metformin activates adenosine monophosphate-activated protein kinase (AMPK) an important regulator of several metabolic pathways resulting in enhanced glucose utilisation, reduction of protein synthesis and improvement of mitochondrial function. Furthermore, metformin has been shown to reduce collagen accumulation and potentially reduce LV hypertrophy and improve diastolic function in the diabetic myocardium. The cardio protection afforded by metformin treatment seems to result from interference with TGF-beta signaling pathway and activation of the AMP-kinase signaling cascade. A recent systematic review and meta regression analysis have shown that metformin treatment was associated with a reduction in mortality in patients with HFpEF. In addition, treatment with metformin of non-diabetic metabolic syndrome patients with diastolic dysfunction, on top of lifestyle counseling, was associated with improved diastolic function. Moreover, some studies have shown that metformin can reduce body weight. However, metformin has not been officially approved as a medicine for weight loss because its effect on different populations remains inconsistent. No studies to date assessed the role of metformin in obese non-diabetic patients with HFpEF Accordingly, investigators aimed to evaluate if metformin can improve diastolic function in non-diabetic obese patients with HFpEF. Investigators also aimed to assess the impact of this therapy in functional capacity, weight loss and health-related quality of life (HRQoL).

Study Type

Interventional

Enrollment (Estimated)

80

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Egypt
      • Cairo, Egypt
        • Recruiting
        • Cairo University Hospitala
        • Contact:
      • Cairo, Egypt
        • Not yet recruiting
        • Cairo University Hospitals
        • Contact:
        • Sub-Investigator:
          • Shereen Elgengeehy, Prof.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • - Inclusion criteria:

    • Age of 40 years to 74 years.
    • HFpEF (≥ 50%)
    • Written informed consent of the subject to participate in the study.
    • New York Heart Association functional class II-IV.
    • Body mass index ≥ 30 Kg/m2

Exclusion Criteria:

  • - Exclusion criteria:

    • Patients with heart failure with reduced ejection fraction (< 40%)
    • Age less than 40 and more than 74
    • New York Heart Association functional class I
    • Body mass index < 30 Kg/m2
    • Diabetic patients or prior metformin user
    • Renal impairment
    • Known allergy to metformin
    • End- stage liver disease
    • Cancer
    • Pregnancy or lactation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: control
Lifestyle counseling plus standard evidence based therapy
Experimental: intervention (metformin)
Lifestyle counseling plus standard evidence based therapy and metformin (target dose 1000 mg bid)
Drug: Metformin
The intervention will consist in giving metformin starting with 500 mg once daily (at breakfast) during the first week; if well tolerated, the dose was progressively increased to 500 mg twice daily (at breakfast and dinner) during week 2, to 1000 mg at breakfast and 500 mg at dinner during week 3, in order to reach the target dose of 1000 mg twice daily (at breakfast and dinner)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The change in the mean early diastolic mitral annular velocity (mean e'), at 3 and 6 months
Time Frame: baseline, 3 and 6 months
Mean early diastolic mitral annular velocity assessed by echocardiography
baseline, 3 and 6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
HRQOL (MLFHQ) adverse effects of metformin hospitalization rate Change in N-terminal pro-BNP (NT-proBNP) and Change in body weight
Time Frame: baseline, 3 and 6 months
HRQOL using Minnesota Living with Heart Failure Questionnaire for quality-of-life evaluation (MLFHQ)
baseline, 3 and 6 months
adverse effects of metformin
Time Frame: baseline, 3 and 6 months
lactic acidosis side effects : dyspnea, muscle cramps, abdominal pain ,hypothermia or asthenia
baseline, 3 and 6 months
hospitalization rate
Time Frame: baseline, 3 and 6 months
hospitalization rate
baseline, 3 and 6 months
Change in N-terminal pro-BNP (NT-proBNP)
Time Frame: baseline, 3 and 6 months
Change in N-terminal pro-BNP (NT-proBNP)
baseline, 3 and 6 months
Change in body weight
Time Frame: baseline, 3 and 6 months
Change in body weight (BMI)
baseline, 3 and 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sara ElAdawy

Collaborators

Cairo University

Investigators

  • Study Director: sara Eladawy, PhD, MSA University
  • Principal Investigator: Naglaa Bazan, Ass. Prof, Cairo University Hospitals
  • Study Chair: shreen Elgengeehy, Prof., Cairo University Hospitals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2023

Primary Completion (Estimated)

October 10, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

April 16, 2023

First Submitted That Met QC Criteria

April 26, 2023

First Posted (Actual)

May 6, 2023

Study Record Updates

Last Update Posted (Actual)

October 11, 2023

Last Update Submitted That Met QC Criteria

October 8, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RSPL1.5

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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