The Effect of Addition of Metformin to SGLT2 In Diabetic Patients With Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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a prospective open-label, randomized controlled study to evaluate the efficacy of the addition of metformin to SGLT2 in diabetic patient with preserved ejection fraction

Detailed Description
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Regardless of the benefits noted with SGLT2is, metformin is recommended as first-line therapy for glycemic control in individuals with T2DM and HF, including HFpEF, with estimated glomerular filtration rates (eGFRs) ≥30 mL/min/1.73 m2. This is based on the demonstrated experience with long-term use; its safety, low cost, and low side effect profile; as well as observational (not clinical trial) data suggesting a 20% relative risk reduction in mortality in individuals with HF, including HFpEF. Nevertheless, it is worth mentioning that 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. Nevertheless, a recent met analysis showed that initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy. based on that we our aim is to evaluate the efficacy of the addition of metformin to SGLT2 in diabetic patient with preserved ejection fraction

Official Title
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The Effect of Addition of Metformin to SGLT2 In Diabetic Patients With Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure With Preserved Ejection Fraction, Diabete Type 2

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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 I-IV. Diabetic patients SGL-2 naive. Newly diagnosed heart failure of preserved ejection fraction Exclusion Criteria: Patients with heart failure with reduced ejection fraction (< 40%) Age less than 40 and more than 74 GFR < 30 mL/min A1c > 9 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: control(SGLT2i/ARBs/MRA/ +/- diuretics).<br>Lifestyle counseling plus standard evidence-based therapy for HFpEF (SGLT2i/ARBs/MRA/ +/- diuretics). | |
| Experimental: intervention<br>Lifestyle counseling plus standard evidence-based therapy for HFpEF (SGLT2i/ARBs/MRA/ +/- diuretics)+ metformin | Drug: Metformin<br>* The intervention will consist in giving metformin starting with 500 mg once daily 1 gm 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) during the rest of the follow-up. Patients will be followed up by telephone call 2 weeks intervals during the study period 5 SGL-2 will be prescribed to group 1 after diagnosis with HFpEF while group 2 will have SGL-2 and Metformin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalization rate | Hospitalization rate | baseline, 3 and 6 months | 
| HRQOL using Minnesota Living with Heart Failure Questionnaire for quality-of-life evaluation (MLFHQ) | HRQOL using Minnesota Living with Heart Failure Questionnaire for quality-of-life evaluation (MLFHQ) | baseline, 3 and 6 months | 

Secondary 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 | The change in the mean early diastolic mitral annular velocity (mean e'), at 3 and 6 months | baseline, 3 and 6 months | 
| adverse drug effects | adverse drugs effects | 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 | 
| Neutrophil/lymphocyte ratio -AMPK pathway | Neutrophil/lymphocyte ratio -AMPK pathway | baseline, 3 and 6 months | 
| Inflammatory and oxidative stress | Inflammatory and oxidative stress | baseline, 3 and 6 months | 
| Change in body weight | Change in body weight | baseline, 3 , 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, SGLTi, HFpEF