Diastolic DysfunctionPhase 2NCT05847244
The Effect of Addition of Metformin In Obese Non- Diabetic Patients With Heart Failure With Preserved Ejection Fraction
A Phase 2 study testing Metformin in people with Diastolic Dysfunction and Obesity, run by Sara ElAdawy at 2 sites in Egypt.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 40 to 74 years
- Conditions the study is for
- Diastolic Dysfunction, Obesity
- What is being tested?
- Metformin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 2 sitesEgypt
- Study dates
- 1 Oct 2023to 1 Dec 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 74 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- - 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
Who cannot join
- - 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
Show all 11Show fewer
- Renal impairment
- Known allergy to metformin
- End- stage liver disease
- Cancer
- Pregnancy or lactation
Trial locations and contacts
2 sites in 1 country.
Egypt2 sites, 2 recruiting
- Recruiting
Cairo University Hospitala
Cairo
naglaa bazan, ass.prof, 01005807504, naglaabazan@cu.edu.eg
- Not yet recruiting
Cairo University Hospitals
Cairo
naglaa bazan, Ass.prof, 01005807504, naglaabazan@cu.edu.eg
Shereen Elgengeehy, Prof.
About this study
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.
Read the 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).
- Conditions
- Diastolic Dysfunction, Obesity
- Being tested
- Metformin
- Keywords
- metformin, obesity, diastolic dysfunction
- Medical subject headings
- Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| control | No intervention | Lifestyle counseling plus standard evidence based therapy |
| intervention (metformin) | Experimental | Lifestyle counseling plus standard evidence based therapy and metformin (target dose 1000 mg bid) Receives: Drug: Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: baseline, 3 and 6 months
Secondary outcomes (5)
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)
Measured: baseline, 3 and 6 months
adverse effects of metformin
lactic acidosis side effects : dyspnea, muscle cramps, abdominal pain ,hypothermia or asthenia
Measured: baseline, 3 and 6 months
hospitalization rate
hospitalization rate
Measured: baseline, 3 and 6 months
Change in N-terminal pro-BNP (NT-proBNP)
Change in N-terminal pro-BNP (NT-proBNP)
Measured: baseline, 3 and 6 months
Change in body weight
Change in body weight (BMI)
Measured: baseline, 3 and 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2023
- Study start1 Oct 2023
- Primary completion10 Oct 2024 (estimated)
- Study completion1 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Diastolic DysfunctionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- prospective open-label, randomized controlled study
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sara ElAdawy
- Sponsor type
- University, hospital or other
- Collaborators
- Cairo University
- Responsible party
- Sponsor-investigator, Sara ElAdawy, October University for Modern Sciences and Arts
- Investigators
- sara Eladawy, PhD, Study director, MSa universityNaglaa Bazan, Ass. Prof, Principal investigator, Cairo Universityshreen Elgengeehy, Prof., Study chair, Cairo University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05847244
- Sponsor's protocol ID
- RSPL1.5
- Status last verified
- Oct 2023
- First submitted
- 16 Apr 2023
- Last updated
- 11 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Pu R, Shi D, Gan T, Ren X, Ba Y, Huo Y, Bai Y, Zheng T, Cheng N. Effects of metformin in obesity treatment in different populations: a meta-analysis. Ther Adv Endocrinol Metab. 2020 May 21;11:2042018820926000. doi: 10.1177/2042018820926000. eCollection 2020.
PubMed 32499908Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ, Jordan HS, Kendall KA, Lux LJ, Mentor-Marcel R, Morgan LC, Trisolini MG, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;129(25 Suppl 2):S102-38. doi: 10.1161/01.cir.0000437739.71477.ee. Epub 2013 Nov 12. No abstract available.
PubMed 24222017Ladeiras-Lopes R, Sampaio F, Leite S, Santos-Ferreira D, Vilela E, Leite-Moreira A, Bettencourt N, Gama V, Braga P, Fontes-Carvalho R. Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: the MET-DIME randomized trial. Endocrine. 2021 Jun;72(3):699-710. doi: 10.1007/s12020-021-02687-0. Epub 2021 Apr 8.
PubMed 33830437Halabi A, Sen J, Huynh Q, Marwick TH. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020 Aug 5;19(1):124. doi: 10.1186/s12933-020-01100-w.
PubMed 32758236
Study at a glance
From the registry record, last updated by the sponsor on 11 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Addition of Metformin In Obese Non- Diabetic Patients With Heart Failure With Preserved Ejection Fraction
- ClinicalTrials.gov ID
- NCT05847244
- Acronym / sponsor ID
- RSPL1.5
- Conditions
- Diastolic Dysfunction, Obesity
- Keywords
- metformin, obesity, diastolic dysfunction
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Sara ElAdawyUniversity, hospital or other
- Collaborators
- Cairo University
- Study start
- 1 Oct 2023 (actual)
- Primary completion
- 10 Oct 2024 (estimated)
- Study completion
- 1 Dec 2024 (estimated)
- First posted
- 6 May 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- prospective open-label, randomized controlled study
| Arm | Type | Receives |
|---|---|---|
| control | No intervention | –Lifestyle counseling plus standard evidence based therapy |
| intervention (metformin) | Experimental | Drug: MetforminLifestyle counseling plus standard evidence based therapy and metformin (target dose 1000 mg bid) |
Who may qualify
- Ages
- 40 to 74 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- - Inclusion criteria:
Key exclusion criteria (11 listed)
- - Exclusion criteria:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminThe 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) | Drug | intervention (metformin) |
Primary outcome
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
5 secondary outcomes
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
adverse effects of metformin
Time frame: baseline, 3 and 6 months
hospitalization rate
Time frame: baseline, 3 and 6 months
Change in N-terminal pro-BNP (NT-proBNP)
Time frame: baseline, 3 and 6 months
Change in body weight
Time frame: baseline, 3 and 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Oct 2023.
- Results publication: PubMed 32499908Pu R, Shi D, Gan T, Ren X, Ba Y, Huo Y, Bai Y, Zheng T, Cheng N. Effects of metformin in obesity treatment in different populations: a meta-analysis. Ther Adv Endocrinol Metab. 2020 May 21;11:2042018820926000. doi: 10.1177/2042018820926000. eCollection 2020.
- Results publication: PubMed 24222017Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ, Jordan HS, Kendall KA, Lux LJ, Mentor-Marcel R, Morgan LC, Trisolini MG, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;129(25 Suppl 2):S102-38. doi: 10.1161/01.cir.0000437739.71477.ee. Epub 2013 Nov 12. No abstract available.
- Results publication: PubMed 33830437Ladeiras-Lopes R, Sampaio F, Leite S, Santos-Ferreira D, Vilela E, Leite-Moreira A, Bettencourt N, Gama V, Braga P, Fontes-Carvalho R. Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: the MET-DIME randomized trial. Endocrine. 2021 Jun;72(3):699-710. doi: 10.1007/s12020-021-02687-0. Epub 2021 Apr 8.
- Results publication: PubMed 32758236Halabi A, Sen J, Huynh Q, Marwick TH. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020 Aug 5;19(1):124. doi: 10.1186/s12933-020-01100-w.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
sara Eladawy, PhD study director
MSa university
Naglaa Bazan, Ass. Prof principal investigator
Cairo University
shreen Elgengeehy, Prof. study chair
Cairo University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin in people with Diastolic Dysfunction and Obesity, run by Sara ElAdawy at 2 sites in Egypt.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Egypt. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact sara eladawy, PhD (01222124567, smeladway@msa.edu.eg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The change in the mean early diastolic mitral annular velocity (mean e'), at 3 and 6 months (time frame: baseline, 3 and 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05847244, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Oct 2023.