Metformin for Heart Failure

(Met-PEF Trial)

Not currently recruiting at 1 trial location

Overseen By Michael B Nelson

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Wake Forest University Health Sciences

Must not be taking: Antidiabetics, Antibiotics

Disqualifiers: Diabetes, Hypertension, COPD, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 20 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine how metformin, a common diabetes medication, affects individuals with a specific type of heart failure known as HFpEF. Researchers seek to discover if metformin can enhance physical function, improve quality of life, and reduce inflammation and gut issues in these patients. Participants will receive either metformin or a placebo (a harmless pill resembling the real medicine) for 20 weeks. Suitable candidates have stable heart failure symptoms, no diabetes, and a body mass index of 25 or above. As a Phase 2 trial, this research focuses on assessing metformin's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that your heart failure symptoms and medications have been stable for at least 3 weeks before joining. However, the protocol does not specify if you need to stop any current medications, so it's best to discuss this with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that metformin is safe for people with heart failure. Studies have found that it can even reduce the risk of death and other heart-related health issues. Often used to treat diabetes, metformin is known for its safety. Patients generally find it easy to take, especially in extended-release forms, which help reduce stomach problems. Most people can take it without major side effects if they follow the instructions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Researchers are excited about using metformin for heart failure because it offers a new approach to managing the condition. Unlike traditional heart failure treatments that typically focus on managing symptoms and fluid retention with medications like diuretics and beta-blockers, metformin is known for its role in controlling blood sugar and improving insulin sensitivity. This unique mechanism may provide additional cardiovascular benefits, potentially improving heart function and patient outcomes. Additionally, metformin's well-established safety profile and the use of an extended-release formulation enhance patient compliance by reducing gastrointestinal side effects.

What evidence suggests that metformin might be an effective treatment for heart failure?

Research has shown that metformin might help people with heart failure. Studies have found that metformin can protect the heart, especially in those with type 2 diabetes. It appears to work by improving insulin use and reducing inflammation, which can harm the heart. Some research also suggests that metformin might improve heart function and outcomes for heart failure patients. In this trial, participants will receive either metformin or a placebo to further investigate these potential benefits. Although these results are promising, more research is needed to fully understand how metformin aids in heart failure. ^{1 2 3 6 7}

Who Is on the Research Team?

Dalane W. Kitzman, MD

Principal Investigator

Wake Forest University Health Sciences

Are You a Good Fit for This Trial?

This trial is for people aged 60 or older with heart failure where the heart pumps normally (HFpEF). They must have stable symptoms and not be on metformin or other diabetes drugs, have a BMI of 25 or higher, normal blood pressure and kidney function, no significant anemia, acidosis, diabetes, severe lung disease, recent cancer treatments or certain heart conditions. Participants should not plan to move away within a year.

Inclusion Criteria

My heart's left ventricle has mild dysfunction.

Final eligibility based on review of hospital and outpatient records, history, physical examination, echocardiogram, and familiarization/screening exercise test by a board-certified investigator cardiologist with extensive experience in heart failure investigations in older persons with HFpEF

I have heart failure with a normal heart pumping function.

Exclusion Criteria

Plans to leave area within 1 year

Your body mass index (BMI) is less than 25.0.

Your hemoglobin level is less than 9.5 grams.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive metformin or placebo for 20 weeks, with dose escalation over the first 3 weeks

20 weeks

1 visit (in-person) at week 4, bi-weekly virtual assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person) at week 20

What Are the Treatments Tested in This Trial?

Interventions

• Metformin
• Placebo

Trial Overview The Met-PEF study tests if taking metformin (1500 mg/day) for 20 weeks improves physical function, quality of life, gut health and reduces inflammation in older patients with HFpEF. It's a blind test where half the participants will get metformin and half will get a fake pill without knowing which one they're taking.

How Is the Trial Designed?

Group I: Metformin Active Control 1 Intervention

20 weeks of metformin 1500 mg daily. Metformin is a widely used medication with an excellent safety profile. Dosing will be escalated during the first 3 weeks of treatment. Dosing will be initiated with 500 mg taken orally once daily in the evening for 1 week. After one week, the participant will be called to assess tolerance and will be asked to increase dose to two capsules per day for a total 1000 mg per day for one week. At the end of the second week, participants will be called again and if they tolerated the increased dose will be instructed to increase to three capsules (1500 mg/day) per day for the remainder of the 20 weeks. An extended release formulation will be used which improves compliance and reduces GI side effects.

Group II: Placebo Placebo Group 1 Intervention

20 weeks of placebo 1500 mg daily. Placebo is a biologically inert substance placed in capsules to match appearance of active intervention (metformin). Dosing will be escalated during the first 3 weeks of treatment. Dosing will be initiated with 500 mg taken orally once daily in the evening for 1 week. After one week, the participant will be called to assess tolerance and will be asked to increase dose to two capsules per day for a total 1000 mg per day for one week. At the end of the second week, participants will be called again and if they tolerated the increased dose will be instructed to increase to three capsules (1500 mg/day) per day for the remainder of the 20 weeks.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

University of South Florida

Collaborator

Trials

433

Recruited

198,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

SGLT2 inhibitors have been shown to significantly reduce the risk of developing and worsening heart failure in patients, including those without diabetes, based on recent trials.

Unlike other antidiabetic agents, SGLT2 inhibitors provide additional benefits for heart failure patients, potentially lowering hospitalization rates and improving overall survival when used alongside standard heart failure treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of antidiabetic agents on heart failure. Wijnen, M., Duschek, EJJ., Boom, H., et al.[2022]

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, are effective and safe options for lowering blood sugar in type 2 diabetes, often used alongside other medications like metformin.

While these therapies have shown cardiovascular safety in clinical trials, there are concerns about their use in patients with heart failure, highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incretin-Based Therapy for Diabetes: What a Cardiologist Needs to Know. Waldrop, G., Zhong, J., Peters, M., et al.[2018]

In a study involving 1,499,650 patients with diabetes, the use of incretin-based drugs (DPP-4 inhibitors and GLP-1 analogues) did not increase the risk of hospitalization for heart failure compared to traditional oral antidiabetic drug combinations.

The analysis showed consistent results for both patients with and without a history of heart failure, indicating that incretin-based therapies are safe in terms of heart failure risk in this large population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. Filion, KB., Azoulay, L., Platt, RW., et al.[2022]

Newer diabetes medications, such as DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors, are being studied for their potential benefits in patients with heart failure, a condition that affects 25-35% of those with type 2 diabetes.

These drug classes are not only being evaluated for cardiovascular safety but also for their impact on heart function, quality of life, and progression of heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating Diabetes in Patients with Heart Failure: Moving from Risk to Benefit. DeFilippis, EM., Givertz, MM.[2019]

There is a significant gap in the use of life-saving therapies for patients with heart failure with reduced ejection fraction, despite clear evidence that guideline-directed medical therapy (GDMT) and comprehensive disease-modifying medical therapy (CDMMT) improve patient outcomes.

Newer therapies, such as angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors, show promise in enhancing efficacy and safety for heart failure treatment, yet their optimal use is not being fully realized globally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Gap to Fill: Rationale for Rapid Initiation and Optimal Titration of Comprehensive Disease-modifying Medical Therapy for Heart Failure with Reduced Ejection Fraction. Brownell, NK., Ziaeian, B., Fonarow, GC.[2021]

The analysis of the US-FDA Adverse Event Reporting System revealed a statistically significant association between the use of dipeptidyl peptidase-4 inhibitors (DPP-4-Is) and heart failure (HF), particularly with saxagliptin and vildagliptin, indicating a potential safety concern for these medications.

Despite the overall association, the findings suggest that while saxagliptin and vildagliptin show a higher risk for HF, sitagliptin's risk is less clear and may require further investigation, highlighting the need for ongoing monitoring of cardiovascular safety in DPP-4-I treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. Raschi, E., Poluzzi, E., Koci, A., et al.[2017]

A recent observational study found that metformin therapy is associated with improved outcomes in patients with diabetes and heart failure, suggesting it may be beneficial for this population.

Metformin is already recognized as a first-line treatment for Type 2 diabetes due to its efficacy, safety, and ability to reduce mortality in newly diagnosed patients, making its positive effects in heart failure particularly noteworthy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wrongfully accused: metformin use in heart failure. Eurich, DT., McAlister, FA.[2011]

GLP-1 agonists and DPP-4 inhibitors, commonly used for diabetes, may also provide benefits for heart failure due to their effects on glucose metabolism and insulin sensitivity, which are linked to both conditions.

Early pilot studies suggest that GLP-1 agonists could improve heart function, blood flow, and quality of life in heart failure patients, leading to ongoing phase II clinical trials to further investigate these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incretin-related drug therapy in heart failure. Vest, AR.[2021]

Recent studies have raised concerns about the cardiovascular safety of DPP4 inhibitors, particularly saxagliptin, which was associated with a 27% increase in hospitalizations for heart failure among diabetic patients in the SAVOR-TIMI 53 trial.

Despite earlier concerns, newer large-scale clinical trials have provided more insights into the effects of DPP4 inhibitors on heart failure, suggesting a need to further understand their role in managing cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of dipeptidyl peptidase-4 inhibitors: recent evidence on heart failure. Kankanala, SR., Syed, R., Gong, Q., et al.[2020]

DPP-4 inhibitors and GLP-1 receptor agonists can significantly improve exercise tolerance in heart failure patients, as shown in a systematic review of four trials involving 659 patients.

These medications do not negatively impact quality of life or increase the risk of serious adverse events or mortality, suggesting they may be a safe option for heart failure patients, especially those with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the DPP-4-GLP-1 pathway improves exercise tolerance in heart failure patients: a systematic review and meta-analysis. Chen, C., Huang, Y., Zeng, Y., et al.[2023]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0026049522000385

Metformin and the heart: Update on mechanisms of ... Review. Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure.

2. jacc.org jacc.org/doi/10.1016/j.jchf.2021.11.001

Clinical Outcomes With Metformin and Sulfonylurea ... Metformin initiation ; Heart failure medical therapy at discharge ; ACE inhibitor/ARB, 355 (78.7), 3,806 (71.8) ; Beta-blocker, 368 (81.1), 4,413 ( ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8698925/

Effects of Metformin in Heart Failure - PubMed Central - NIH Mechanisms of Beneficial Impact of Metformin on Heart Failure. The current knowledge supports a protective role of metformin against HF based on a series of ...

4. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.040144

Metformin Use and Clinical Outcomes Among Patients With ... Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23508758/

Comparative safety and effectiveness of metformin in ... Background: There is an ongoing controversy regarding the safety and effectiveness of metformin in the setting of heart failure (HF).

6. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15737

The safe use of metformin in heart failure patients both with ... Metformin appears to be safe to use in heart failure patients if the plasma metformin and lactate concentrations are maintained below 5 mg/L and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4295739/

Cardiovascular Safety Profile of Currently Available Diabetic ... Metformin showed a significantly greater effect than chlorpropamide, glibenclamide, or insulin on any diabetes-related endpoint, all-cause mortality, and stroke ...