Metformin for Heart Failure

(Met-PEF Trial)

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

80 Participants Needed

Trial Summary

What is the purpose of this trial?

Met-PEF will be a randomized, double-blind, placebo-controlled trial to examine the effects of 20 weeks of 1500 mg/day of metformin on physical function, quality of life (QOL), microbiome diversity, leaky gut, and systemic inflammation in patients with 80 older patients with heart failure with preserved ejection fraction (HFpEF).

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.

What data supports the effectiveness of the drug Metformin for heart failure?

Research indicates that Metformin, commonly used for diabetes, has shown improved outcomes in patients with both diabetes and heart failure, suggesting potential benefits for heart failure patients. ^{1 2 3 4 5}

Is Metformin safe for use in humans?

The research articles provided do not contain specific safety information about Metformin or its other names like Glucophage, Fortamet, Glumetza, or Riomet. They focus on other antidiabetic drugs and their effects on heart failure. ^{1 5 6 7 8}

How does the drug Metformin differ from other treatments for heart failure?

Metformin is unique because it is primarily used to control blood sugar in type 2 diabetes, but it has shown potential benefits in heart failure patients by improving outcomes and reducing mortality, unlike some other diabetes drugs that may increase heart failure risk. ^{1 4 5 9 10}

Research Team

Dalane W. Kitzman, MD

Principal Investigator

Wake Forest University Health Sciences

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treating Diabetes in Patients with Heart Failure: Moving from Risk to Benefit. [2019]

2. England 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. [2023]

3. England 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. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Wrongfully accused: metformin use in heart failure. [2011]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of antidiabetic agents on heart failure. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Incretin-Based Therapy for Diabetes: What a Cardiologist Needs to Know. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

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

10. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of dipeptidyl peptidase-4 inhibitors: recent evidence on heart failure. [2020]