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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests metformin, a common diabetes medication, to determine if it can prevent or reduce heart tissue scarring (cardiac fibrosis) in people with PAI-1 deficiency, a specific genetic condition. Participants will either take metformin daily or join a group that does not receive the medication. The trial suits individuals aware of their PAI-1 deficiency who wish to explore metformin's potential impact on their heart health over five years. As a Phase 4 trial, metformin is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

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.

What is the safety track record for metformin?

Research has shown that metformin is generally safe for use and is often prescribed to lower blood sugar levels. One study found that metformin can reduce stress on the heart and lower the risk of new heart problems. Another study showed that metformin can slow or even prevent the development of scarring in heart tissue.

Overall, metformin is considered safe for long-term use and has been used by many patients for various health issues without major problems. However, like any medication, it can have side effects. Prospective participants should discuss any concerns and their health history with the study team before joining. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about metformin for cardiac fibrosis because it offers a new approach compared to traditional treatments like ACE inhibitors and beta-blockers, which primarily focus on managing symptoms and slowing disease progression. Metformin, typically known as a diabetes medication, is being explored for its potential to reduce cardiac fibrosis by targeting metabolic pathways associated with inflammation and fibrosis. This unique mechanism could offer a dual benefit in patients with both diabetes and cardiac fibrosis, potentially improving heart health directly rather than just managing symptoms.

What is the effectiveness track record for metformin in treating cardiac fibrosis?

Studies have shown that metformin can help treat heart tissue scarring, known as cardiac fibrosis. In one study, metformin significantly reduced this scarring in mice, preventing the thickening and hardening of heart tissue. Another study found that metformin could stop or slow the formation of scar tissue and improve heart health in people with heart failure. Metformin blocks a protein called TGFβ1, which causes scarring. In this trial, participants in the Metformin Treatment Group will receive daily metformin to evaluate its potential to manage or reduce heart tissue scarring. ^{5 6 7 8 9}

Who Is on the Research Team?

Sweta Gupta, MD, MS, MBBS

Principal Investigator

Indiana Hemophilia and Thrombosis Center, Inc

Magdalena Lewandowska, MD

Principal Investigator

Indiana Hemophilia and Thrombosis Center, Inc

Amy D Shapiro, MD

Principal Investigator

Indiana Hemophilia and Thrombosis Center, Inc

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0891584923004999

Metformin suppresses cardiac fibroblast proliferation under ... Metformin treatment markedly attenuated cardiac fibrosis in db/db mice and the proliferation and migration of CFs under high-glucose conditions.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12069290/

Comparison of the effects of metformin and empagliflozin ... Recent evidence suggests that empagliflozin (EMPA) and metformin (MET) may improve prognosis in heart failure with preserved ejection fraction (HFpEF) patients.

3. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1155/2021/6673525

Metformin and Fibrosis: A Review of Existing Evidence and ... In this study, researchers found that metformin treatment effectively prevented and slowed the progression of fibrosis, and impressively, it was ...

4. academic.oup.com academic.oup.com/cardiovascres/article/87/3/504/302519

Metformin attenuates cardiac fibrosis by inhibiting the TGFβ 1 Metformin inhibited cardiac fibrosis (fibrosis area/total heart area: 0.6 ± 0.3 vs. 3.6 ± 0.9%, P < 0.01) induced by pressure overload and improved cardiac ...

5. karger.com karger.com/crd/article/130/1/52/80440/The-Effect-of-Metformin-on-Cardiac-Fibrosis-via

The Effect of Metformin on Cardiac Fibrosis via ... Many studies have shown that treatment with metformin improves cardiovascular outcomes and limits atherosclerosis in overweight patients with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8102119/

Metformin and Fibrosis: A Review of Existing Evidence and ... In this study, researchers found that metformin treatment effectively prevented and slowed the progression of fibrosis, and impressively, it was ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9549498/

Protective effects of metformin in various cardiovascular ... This trial found that long‐term metformin exposure significantly reduced left ventricular (LV) mass index and the risk of new onset of ...

8. onlinecjc.ca onlinecjc.ca/article/S0828-282X(24)00751-7/fulltext

TARGETING CARDIAC FIBROSIS WITH METFORMIN IN ... Metformin has a strong safety record and is used primarily for its glucose-lowering efficacy. ... data regarding the cellular mechanism of fibrosis development in ...

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

Metformin Use and Clinical Outcomes Among Patients With ... Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting ...