Metformin for Cardiac Fibrosis

Overseen By Nicci Knipe

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Indiana Hemophilia &Thrombosis Center, Inc.

Must not be taking: Cimetidine, Dolutegravir, Patiromer, others

Disqualifiers: Renal dysfunction, Alcohol abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 60 months

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the efficacy and safety of metformin, in patients 18-65 years of age with homozygous plasminogen activator inhibitor-1 (PAI-1) deficiency, with or without cardiac fibrosis, for a period of 60 months. The starting dose of metformin will be 500 mg up to a maximum dose of 2000 mg for a period of 5 years with the aim to assess the safety and efficacy of metformin on prevention/stabilization or regression of cardiac fibrosis in a Treated population vs. a Comparison population.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications like cimetidine, dolutegravir, patiromer, ranolazine, or tafenoquine if no alternative therapy is possible. If you are on these medications, you may need to discuss alternatives with your doctor.

Is Metformin safe for humans?

Metformin is generally considered safe for humans when used as prescribed, with a low risk of serious side effects if contraindications, like kidney issues, are observed. It is well-tolerated, though some people may experience mild stomach problems, and it has been shown to have heart-protective benefits in people with diabetes. ^{1 2 3 4 5}

How does the drug Metformin differ from other treatments for cardiac fibrosis?

Metformin is unique in treating cardiac fibrosis because it works by inhibiting the TGFbeta1-Smad3 signaling pathway, which is involved in the development of fibrosis. Unlike other treatments, Metformin is primarily known as a diabetes medication, but it is being explored for its potential to prevent heart-related issues, including cardiac fibrosis. ^{6 7 8 9 10}

Research Team

Magdalena Lewandowska, MD

Principal Investigator

Indiana Hemophilia and Thrombosis Center, Inc

Sweta Gupta, MD, MS, MBBS

Principal Investigator

Indiana Hemophilia and Thrombosis Center, Inc

Amy D Shapiro, MD

Principal Investigator

Indiana Hemophilia and Thrombosis Center, Inc

Eligibility Criteria

Adults aged 18-65 with a confirmed genetic mutation for PAI-1 deficiency can join this trial. They must be willing to take metformin daily or just be observed without the drug, and able to follow study rules. People with kidney issues, allergies to metformin, alcohol use problems, or taking certain drugs can't participate.

Inclusion Criteria

Have read, understood and be able to provide written informed consent

I have a confirmed genetic mutation related to PAI-1 deficiency.

I understand and agree to follow the study's requirements.

Exclusion Criteria

Inability to understand and provide written informed consent

Unwillingness to avoid alcohol

I am taking cimetidine, dolutegravir, patiromer, ranolazine, or tafenoquine and cannot switch medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

12 months

1 visit (in-person)

Treatment

Participants receive daily metformin treatment with doses ranging from 500 mg to 2000 mg, or are observed without treatment

60 months

Monthly visits initially, then every 3 months

Interim Analysis

Safety analysis conducted at 30 months

1 month

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Annual visits

Treatment Details

Interventions

• Metformin

Trial Overview The trial is testing if extended-release metformin tablets (500 mg up to 2000 mg) over five years can prevent or reduce heart scarring in patients with PAI-1 deficiency. Participants will either receive metformin treatment or no drug for observation.

Participant Groups

Group I: Metformin Treatment Group Experimental Treatment 1 Intervention

Subjects with PAI-1 deficiency with or without cardiac fibrosis, receiving daily treatment with metformin for a daily range of 500-2000mg

Group II: Observation Group Active Control 1 Intervention

Subjects with PAI-1 deficiency with or without cardiac fibrosis, not receiving treatment with metformin Subjects are allowed to switch between the two groups

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?

Indiana Hemophilia &Thrombosis Center, Inc.

Lead Sponsor

Trials

6

Recruited

690+

Findings from Research

GLP-1 receptor agonists like liraglutide, dulaglutide, and semaglutide have been shown to significantly reduce the risk of major cardiovascular events in patients with type 2 diabetes at high cardiovascular risk, based on robust cardiovascular outcomes trials.

Current diabetes treatment guidelines emphasize the importance of using medications with proven cardiovascular benefits, such as GLP-1 receptor agonists, rather than solely focusing on blood sugar control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Outcomes Trials of Incretin-Based Therapies. Thethi, TK., Bilal, A., Pratley, RE.[2022]

Metformin is a first-line treatment for type 2 diabetes due to its effectiveness in reducing insulin resistance without causing weight gain or hypoglycemia, making it a safe option for patients.

Recent studies have shown that metformin also has cardiovascular benefits and may help in conditions beyond diabetes, such as insulin resistance and potentially tumor suppression, highlighting its broader therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin therapy and clinical uses. Scarpello, JH., Howlett, HC.[2022]

Metformin extended release (ER) provides effective glycaemic control with once-daily dosing, showing similar effectiveness to twice-daily dosing of immediate-release formulations over a 24-week period in clinical trials.

The metformin ER formulation was well tolerated at doses of 1500 and 2000 mg/day, with no increase in adverse events, indicating its safety for patients managing their blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. Schwartz, SL., Wu, JF., Berner, B.[2019]

References

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

Cardiovascular Outcomes Trials of Incretin-Based Therapies. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Metformin therapy and clinical uses. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Cardioprotection by Metformin: Beneficial Effects Beyond Glucose Reduction. [2018]

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

Cardiovascular disease prevention in patients with type 2 diabetes: The role of oral anti-diabetic agents. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. [2019]

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

Liraglutide Attenuates Myocardial Fibrosis via Inhibition of AT1R-Mediated ROS Production in Hypertensive Mice. [2022]

7. China pubmed.ncbi.nlm.nih.gov

Liraglutide Suppresses Myocardial Fibrosis Progression by Inhibiting the Smad Signaling Pathway. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Novel therapeutic targets of metformin: metabolic syndrome and cardiovascular disease. [2022]

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

Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. [2022]