Metformin for Peripheral Arterial Disease

(PERMET Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether metformin, a common diabetes medication, can help individuals with peripheral artery disease (PAD) walk farther in six minutes. PAD is a condition where narrowed blood vessels reduce blood flow to the limbs, causing pain and difficulty walking. Participants will receive either metformin or a placebo (a non-active pill) daily for six months. Ideal candidates have PAD and experience symptoms like pain or discomfort when walking, but do not have other major health issues that restrict walking. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that metformin is generally safe for use. It has served as a common treatment for type 2 diabetes for many years. Some studies suggest that metformin might lower the risk of death from any cause by up to 16%. However, it could slightly increase the risk of stroke.

Metformin's safety is well-established, as the FDA has approved it for diabetes, indicating it has passed numerous safety tests. While side effects can occur with any medication, metformin is considered safe for most people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for peripheral artery disease?

Metformin is unique because, unlike typical treatments for Peripheral Arterial Disease (PAD) that often involve antiplatelet therapy, cholesterol-lowering medications, or surgical interventions, it offers a novel approach by targeting insulin sensitivity and metabolic pathways. Researchers are excited about metformin because it may improve blood flow and reduce inflammation in the arteries, potentially addressing the root metabolic issues that contribute to PAD. This could offer a new avenue for managing the disease, especially for patients who might not respond well to standard therapies.

What evidence suggests that metformin might be an effective treatment for peripheral artery disease?

Research has shown that metformin, which participants in this trial may receive, may help people with peripheral artery disease (PAD) live longer and experience fewer heart problems. However, it does not appear to keep the arteries open. In a study with mice, metformin improved blood flow to the legs but did not significantly enhance walking ability. These findings suggest that while metformin might benefit heart health in PAD patients, its effect on walking remains unclear. Participants in this trial may also receive a placebo as part of the study. ^{1 6 7 8 9}

Who Is on the Research Team?

Mary McDermott, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12493163/

Effect of metformin in a novel experimental model ... In a clinically relevant mouse model of peripheral artery disease, metformin improved hind limb blood supply but not ambulation. The findings suggest that laser ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11434261/

Cardiovascular Effectiveness and Safety of Antidiabetic ... Moreover, in patients who underwent PAD revascularization, SGLT2i showed a lower risk of CV death (HR 0.60, 95% CI 0.40–0.90) but comparable risk of adverse ...

3. ahajournals.org ahajournals.org/doi/10.1161/JAHA.123.034175

Comparison of New‐Onset Peripheral Artery Disease in ... The results demonstrated that SGLT2Is were associated with lower risks of PAD independent of patient's sex, age, baseline metabolic diseases, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03054519

NCT03054519 | Improve PAD PERformance With METformin The PERMET trial will determine whether metformin daily for six months improves six-minute walk performance in individuals with peripheral artery disease ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0890509618305557

Metformin Is Associated with Improved Survival and ... Metformin is associated with improved survival and decreased incidence of adverse cardiac events in PAD patients. However, it did not have an impact on patency ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5552849/

Impact of metformin on cardiovascular disease: a meta- ... According to our review it is possible that metformin reduces risk of all-cause mortality by up to 16% but it could increase risk of stroke by ...

7. ahajournals.org ahajournals.org/doi/10.1161/CIRCINTERVENTIONS.119.008018

Clinical Outcomes in Patients With Type 2 Diabetes ... EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates ...

8. mdpi.com mdpi.com/2077-0383/14/4/1383

Diabetes in Peripheral Artery Disease: Prevalence, ... Five-year mortality rates for patients with both PAD and T2DM reach 23%, more than doubling the risk compared to patients with PAD alone, demonstrating how the ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT01799057

Study Details | NCT01799057 | The Effects of Metformin on ... The purpose of this study is to determine the effects of metformin on functional capacity (pain-free and maximum walking times) in individuals ...