Metformin for Peripheral Arterial Disease

(PERMET Trial)

Recruiting at 4 trial locations

Overseen By Mary McDermott, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Northwestern University

Must not be taking: Metformin

Disqualifiers: Diabetes, Chronic kidney disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

203 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking metformin or have taken it in the past six months.

What data supports the effectiveness of the drug Metformin for Peripheral Arterial Disease?

Research suggests that Metformin, commonly used for type 2 diabetes, may have benefits for Peripheral Arterial Disease (PAD) by improving cardiovascular health and reducing inflammation. It is associated with improved survival and decreased cardiac events, although its impact on limb-specific outcomes is less clear. ^{1 2 3 4 5}

How does the drug Metformin differ from other treatments for peripheral arterial disease?

Metformin is unique for peripheral arterial disease because it is primarily used for type 2 diabetes but has anti-inflammatory and promitochondrial properties that may improve function and slow disease progression in non-diabetic patients. Unlike other treatments, it may also help reduce inflammation and improve mitochondrial function, which are not typical targets of existing therapies for this condition. ^{1 2 3 4 6}

What is the purpose of this trial?

This trial will test if taking metformin daily can help people with peripheral artery disease walk better by improving their blood flow and reducing inflammation. Metformin has been studied for its potential benefits in improving endothelial function and reducing inflammation in various conditions, including type 2 diabetes and peripheral artery disease.

Research Team

Mary McDermott, MD

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for individuals with Peripheral Arterial Disease (PAD). Eligible participants may have had lower extremity revascularization, an Ankle-Brachial Index (ABI) of ≤0.90, or a significant drop in ABI after exercise indicating PAD. Exclusions include those planning major surgeries, with severe illnesses like advanced cancer or lung disease requiring oxygen, dementia, recent heart issues, non-English speakers, amputations above/below the knee, wheelchair users or walker dependence.

Inclusion Criteria

I had surgery to improve blood flow in my legs and my ankle-brachial index drops significantly after exercise.

My ankle-brachial index (ABI) is 0.90 or lower.

Your ankle-brachial index (ABI) is between 0.90 and 1.00, and it drops by 20% or more after doing a specific exercise.

Exclusion Criteria

I have a current ulcer on the bottom of my foot.

I am currently taking or have taken metformin in the last six months.

My vision problems make it hard for me to walk.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metformin or placebo daily for six months to assess improvement in six-minute walk performance

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin
• Placebo

Trial Overview The PERMET trial is testing if taking metformin daily for six months can improve walking performance over a six-minute period compared to a placebo in people with PAD. Participants will be randomly assigned to either receive metformin or a placebo and their walking ability will be measured.

Participant Groups

Group I: Metformin Active Control 1 Intervention

Metformin daily

Group II: Placebo Placebo Group 1 Intervention

Placebo daily for six months.

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?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Findings from Research

The MOBILE IC trial will assess the effects of metformin on 200 non-diabetic veterans with intermittent claudication over 180 days, focusing on improvements in walking distance and overall functional status.

Metformin is hypothesized to reduce systemic inflammation and enhance mitochondrial function, potentially slowing the progression of peripheral artery disease and improving cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol. Reitz, KM., Althouse, AD., Forman, DE., et al.[2023]

In a study of 1204 patients with peripheral arterial disease (PAD), metformin was associated with improved survival rates (60%) and a lower incidence of major adverse cardiac events compared to other diabetes treatments, particularly insulin.

While metformin did not significantly affect limb-specific outcomes like primary and secondary patency or limb salvage rates after interventions, it was linked to better overall cardiovascular health in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Is Associated with Improved Survival and Decreased Cardiac Events with No Impact on Patency and Limb Salvage after Revascularization for Peripheral Arterial Disease. Khan, SZ., Rivero, M., Nader, ND., et al.[2022]

A significant increase in lower extremity amputations (LEA) among diabetic patients was observed, rising by over 25% between 2010 and 2015, which correlates with a decline in glycemic control as indicated by hemoglobin A1c (HbA1c) levels.

Clinical trials, including the ACCORD and LEADER studies, suggest that better glucose control and the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide may reduce the incidence of LEA in people with type 2 diabetes, highlighting the importance of maintaining strict glycemic targets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Up and down waves of glycemic control and lower-extremity amputation in diabetes. Caruso, P., Scappaticcio, L., Maiorino, MI., et al.[2022]

In a study of 187 patients who received non-drug-eluting stents in the superficial femoral or popliteal artery, metformin did not significantly reduce rates of restenosis or the need for reintervention, despite its known endothelial protective effects.

The study followed patients for an average of 13.1 months, and no cases of limb loss were reported, indicating that while metformin has benefits for diabetes management, it may not impact vascular outcomes in this specific context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does Metformin Have an Effect on Stent Patency Rates. Kibrik, P., Alsheekh, A., Izakovich, T., et al.[2022]

Recent cardiovascular outcome trials have shown that novel therapies like GLP-1 receptor agonists (GLP-1 RA) and SGLT2 inhibitors (SGLT2i) provide significant cardioprotective benefits for patients with type 2 diabetes mellitus (T2DM), especially those with peripheral artery disease (PAD).

SGLT2 inhibitors not only improve cardiovascular outcomes but also reduce the risk of heart failure hospitalizations and slow the progression of kidney disease, making them essential in managing high-risk T2DM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contemporary Medical Therapies for Patients with Peripheral Artery Disease and Concomitant Type 2 Diabetes Mellitus: a Review of Current Evidence. Narcisse, DI., Katzenberger, DR., Gutierrez, JA.[2022]

SGLT2 inhibitors and GLP1 receptor agonists have been linked to a significant reduction in major adverse cardiovascular events (MACE) in patients with type 2 diabetes, but patients with peripheral artery disease (PAD) are underrepresented in these studies.

There is a concern regarding an increased risk of amputation associated with canagliflozin, highlighting the need for careful consideration of these medications in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of SGLT2 inhibitors and GLP1-receptor agonists on cardiovascular and limb events in peripheral artery disease: A review. Skeik, N., Elejla, SA., Sethi, A., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Metformin Is Associated with Improved Survival and Decreased Cardiac Events with No Impact on Patency and Limb Salvage after Revascularization for Peripheral Arterial Disease. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Up and down waves of glycemic control and lower-extremity amputation in diabetes. [2022]

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

Does Metformin Have an Effect on Stent Patency Rates. [2022]

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

Contemporary Medical Therapies for Patients with Peripheral Artery Disease and Concomitant Type 2 Diabetes Mellitus: a Review of Current Evidence. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Effects of SGLT2 inhibitors and GLP1-receptor agonists on cardiovascular and limb events in peripheral artery disease: A review. [2023]