Metformin for Peripheral Arterial Disease

(PERMET Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Mary McDermott, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Northwestern University

Must not be taking: Metformin

Disqualifiers: Diabetes, Chronic kidney disease, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

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.

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.

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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.

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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.

I do not speak English.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Northwestern University Chicago, IL

University of Chicago Chicago, IL

Who Is Running the Clinical Trial?

Northwestern University Lead Sponsor

References

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

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol. [2023] Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC.

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] The incidence of cardiovascular and limb-specific adverse outcomes is higher in peripheral arterial disease (PAD) patients with diabetes. Metformin is associated with improved cardiovascular morbidity and mortality. However, the effect of metformin on limb-specific outcomes is unclear. The objective of this study was to assess the effect of metformin on outcomes after intervention for PAD.

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

Up and down waves of glycemic control and lower-extremity amputation in diabetes. [2022] Lower extremity amputations (LEA) are associated with a high mortality and medical expenditure. Diabetes accounts for 45% to 70% of LEA and is one of the most potent risk factors for peripheral artery diseases (PAD). The existence of a link between the recent relaxation of glycemic targets and the resurgence of LEA is suggested from the analysis of adult participants in the National Health and Nutrition Examination Survey (NHANES) between 2010 and 2015, when diabetes-related LEA increased by more than 25% associated with a decline in glycemic control. Indeed, in "the perfect wave" of NHANES, including the years 2007-2010, there was the highest number of diabetic people with hemoglobin A1c (HbA1c), non-high-density lipoprotein (HDL) cholesterol and blood pressure levels at their respective targets, associated with the lowest number of LEA. Until now, the ACCORD study, testing the role of aggressive vs conventional glucose control, and the LEADER trial, evaluating the effects of liraglutide versus placebo, have shown a reduced incidence of LEA in people with type 2 diabetes. The results of ongoing clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1RA, liraglutide or semaglutide) hopefully will tell us whether the wider use of these drugs may provide additional vascular benefits for diabetic people affected by PAD to decrease their risk of LEA.

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

Does Metformin Have an Effect on Stent Patency Rates. [2022] Metformin is the most commonly used drug for type 2 diabetes. Research has shown that metformin also has a protective effect on endothelium by decreasing endothelial vascular reactivity. We hypothesize that metformin will decrease restenosis/reintervention rates in patients receiving lower extremity non-drug-eluting stents (nDESs) in the superficial femoral artery(SFA) and/or popliteal artery.

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] The purpose of this review is to highlight the evidence behind landmark trials involving these two novel drug classes in conjunction with a review of long-standing therapies used to improve cardiovascular (CV) outcomes among patients with peripheral artery disease (PAD) patients and type 2 diabetes mellitus (T2DM).

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] Peripheral artery disease (PAD) and diabetes mellitus are two overwhelming health problems associated with major cardiovascular (CV) and limb events, in addition to increased mortality, despite advances in medical therapies including statins and renin-angiotensin system inhibitors. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1-receptor agonists (GLP1-RA) are two new antihyperglycemic drug classes that have been associated with a significant reduction of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) and CV risk. Whereas most studies had enrolled patients with T2D and concurrent CV disease (CVD), patients with PAD were obviously underrepresented. Furthermore, there was a signal of increased risk of amputation in one of the main trials with canagliflozin. We aim to provide a general review of the current literature and summarize societal guideline recommendations addressing the role of SGLT2i and GLP1-RA drugs in patients with CVD focusing on the PAD population when data are available. Endpoints of interest were MACE and, when available, major adverse limb events (MALE).