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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Obesity, Diastolic Dysfunction

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective open-label, randomized controlled study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: control<br>Lifestyle counseling plus standard evidence based therapy | |
| Experimental: intervention (metformin)<br>Lifestyle counseling plus standard evidence based therapy and metformin (target dose 1000 mg bid) | Drug: Metformin<br>* 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)<br>|

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, obesity, diastolic dysfunction