Metformin for Abdominal Aortic Aneurysm

(LIMIT Trial)

Overseen By Sohrab Sami

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Diabetes medications

Disqualifiers: Diabetes, Metabolic acidosis, Liver disease, others

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: Unknown

Duration: 2 years

314 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

In this research, the investigators are looking at the effects of a drug called metformin may have on the growth of abdominal aortic aneurysm (AAA)s. AAA is an abnormal enlargement of the aorta, which is the large artery in the abdomen (stomach area). The enlargement of the aorta carries a risk that it will rupture and cause life-threatening bleeding in the abdomen (belly). In this study the investigators hope to learn how metformin is associated with the enlargement or change in size of the AAA in study participants. Smaller studies have suggested that metformin may reduce the rate at which aortic aneurysms enlarge. This study will test this question: does metformin prevent AAAs from growing larger?

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 taking medications for diabetes. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

Is Metformin generally safe for humans?

Metformin, also known as Glucophage, is widely used and generally considered safe for treating conditions like type 2 diabetes and gestational diabetes. It is often combined with other medications, like sitagliptin, to improve blood sugar control, and has been approved by the FDA for these uses. ^{1 2 3 4 5}

How does the drug metformin differ from other treatments for abdominal aortic aneurysm?

Metformin is unique because it is primarily used as a diabetes medication but has shown potential in slowing the growth of abdominal aortic aneurysms, which is not a standard treatment for this condition. Unlike other treatments, metformin may reduce the risk of aneurysm enlargement and rupture-related mortality, offering a novel approach to managing this condition. ^{6 7 8 9 10}

What evidence supports the effectiveness of the drug Metformin for treating abdominal aortic aneurysm?

Research suggests that Metformin, a common diabetes medication, may help slow the growth of abdominal aortic aneurysms and reduce the risk of complications, as seen in studies involving diabetic patients. ^{6 7 9 10 11}

Who Is on the Research Team?

Ronald Dalman, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

The LIMIT trial is for men and women aged 55 to 90 with abdominal aortic aneurysms measuring 35-49 mm (men) or 35-45 mm (women). Participants must have stable blood sugar levels (HgbA1c ≤ 6.5%), good kidney function, and be able to take oral medication. Women of childbearing age must use effective contraception.

Inclusion Criteria

My kidney function is good enough to start and continue the trial.

I am between 55 and 95 years old.

For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening, with an agreement to use such a method of contraception during study participation and for an additional 4 weeks after the end of study drug administration.

Exclusion Criteria

You have very low levels of hemoglobin in your blood, less than 10 grams per deciliter.

For female participants of childbearing potential: pregnancy, intent to become pregnant, lactation, or unwilling or unable to use an effective method of contraception

I have had or will have surgery for an abdominal aortic aneurysm.

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, with dosage increasing weekly over the first month

2 years

Regular visits for monitoring and dosage adjustments

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 This study tests whether metformin can prevent the growth of abdominal aortic aneurysms compared to a placebo. Participants will receive either metformin or a placebo and undergo CT scans at the start and end of the study to measure any changes in their aneurysm size.

How Is the Trial Designed?

Group I: Metformin group Active Control 1 Intervention

Participants will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day. Over the first four weeks of the study, you will increase your dosage every week by one pill, so at the end of the first month you will be taking up to four pills per day. If you develop any symptoms or side effects from pill ingestion during this process, your dose will be decreased to the last number of pills you were able to take without developing side effects.

Group II: Placebo Group Placebo Group 1 Intervention

Participants will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day. Over the first four weeks of the study, you will increase your dosage every week by one pill, so at the end of the first month you will be taking up to four pills per day. If you develop any symptoms or side effects from pill ingestion during this process, your dose will be decreased to the last number of pills you were able to take without developing side effects.

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

VA Palo Alto Health Care System

Collaborator

Trials

97

Recruited

58,500+

Kaiser Permanente

Collaborator

Trials

563

Recruited

27,400,000+

Published Research Related to This Trial

In a study involving 266 patients, metformin use in diabetics did not show any significant differences in inflammatory markers or immune cell profiles related to abdominal aortic aneurysm (AAA) formation and growth.

The research indicates that metformin does not appear to influence the peripheral inflammatory environment in patients at risk for or diagnosed with AAA, suggesting that its protective effects against AAA may not be mediated through changes in inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin does not reduce inflammation in diabetics with abdominal aortic aneurysm or at high risk of abdominal aortic aneurysm formation. Wang, SK., Green, LA., Gutwein, AR., et al.[2018]

In a study of 13,834 patients with abdominal aortic aneurysm (AAA) over an average follow-up of 4.2 years, metformin use was associated with a significant 20% reduction in the yearly growth rate of AAA compared to non-users.

The analysis suggests that metformin may be a promising therapy to limit AAA progression, warranting further clinical trials to explore its efficacy in early AAA disease management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population. Itoga, NK., Rothenberg, KA., Suarez, P., et al.[2022]

Metformin significantly reduces the progression of established abdominal aortic aneurysms (AAA) in mice, showing an 85% reduction at 3 days and 68% at 10 days after treatment initiation compared to controls.

The mechanism of action involves AMPK activation, which helps preserve elastin and smooth muscle cells while reducing inflammation, specifically by limiting the differentiation of interferon-γ-producing T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysms. Xu, B., Li, G., Li, Y., et al.[2023]

In a study of 526 patients with small abdominal aortic aneurysms (AAA), those with type 2 diabetes who were prescribed metformin showed a significantly reduced AAA growth rate (1.1 mm/year) compared to non-diabetic patients (2.3 mm/year).

The reduction in AAA growth associated with metformin may be linked to its anti-inflammatory effects, as indicated by lower levels of inflammatory chemokines in patients taking the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Prescription Associated with Reduced Abdominal Aortic Aneurysm Growth Rate and Reduced Chemokine Expression in a Swedish Cohort. Unosson, J., Wågsäter, D., Bjarnegård, N., et al.[2021]

In a study of 306 patients undergoing abdominal aortic aneurysm (AAA) repair, metformin treatment was associated with a significant reduction in repair-related mortality (P = 0.019) and surgical complications (P = 0.032) specifically among patients with diabetes mellitus.

The protective effects of metformin were not observed when comparing all patient groups, indicating that its benefits may be particularly relevant for diabetic patients undergoing AAA repair.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Metformin and Abdominal Aortic Aneurysm Repair Outcomes. Turowicz, A., Kobecki, J., Laskowska, A., et al.[2022]

GLP-1 receptor agonists (GLP-1 RAs) have been shown to significantly reduce major adverse cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk, based on randomized controlled trials and a meta-analysis of six agents.

These medications not only help with glycemic control but also provide additional benefits such as lowering blood pressure, aiding in weight loss, and improving renal outcomes, all while maintaining a low risk of hypoglycemia and no increase in pancreatitis events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future. Ferrari, F., Scheffel, RS., Martins, VM., et al.[2022]

The combination tablet of sitagliptin and metformin (Janumet) has been approved by the FDA for patients with Type 2 diabetes who need better glycemic control, either when taking these medications separately or together.

Sitagliptin has been demonstrated to be safe and effective at a daily dose of 100 mg, and its combination with metformin is believed to enhance glycemic control through complementary mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janumet: a combination product suitable for use in patients with Type 2 diabetes. Reynolds, JK., Neumiller, JJ., Campbell, RK.[2019]

GLP-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control in adults with type 2 diabetes and also provide cardiovascular benefits, with liraglutide and semaglutide demonstrating significant reductions in major adverse cardiovascular events (MACE) in high-risk patients.

The effectiveness of GLP-1 RAs varies, as liraglutide and semaglutide showed clear cardiovascular superiority, while lixisenatide was neutral and exenatide showed only a non-significant trend, indicating that structural differences among these drugs may influence their potency and cardiovascular protective properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect? Li, Y., Rosenblit, PD.[2019]

GLP-1 receptor analogs (GLP-1RAs), particularly semaglutide, have shown significant efficacy in controlling blood sugar levels in type-2 diabetes, with reductions in HbA1c of up to 1.5-1.8%.

Cardiovascular outcome trials indicate that while some GLP-1RAs like liraglutide and semaglutide reduce major adverse cardiovascular events, others like lixisenatide and oral semaglutide show neutral effects, highlighting the variability in cardiovascular benefits among different GLP-1RAs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Cardiovascular Safety of GLP-1 Receptor Analogues. Iqbal, AM., Imamudeen, N., Basheer, A., et al.[2021]

In a feasibility study involving 197 women with gestational diabetes, only 23 were randomized to receive either glibenclamide or insulin alongside metformin, indicating a low recruitment rate of 0.39 women per center per month.

While glibenclamide was well-tolerated with no severe hypoglycemia reported, the combination of metformin and insulin provided better glycemic control compared to metformin and glibenclamide, suggesting that glibenclamide should be reserved for women who cannot use insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glibenclamide and metfoRmin versus stAndard care in gEstational diabeteS (GRACES): a feasibility open label randomised trial. Reynolds, RM., Denison, FC., Juszczak, E., et al.[2021]

A meta-analysis of 10 cohort studies involving 85,050 patients found that metformin significantly limits the expansion of abdominal aortic aneurysms (AAA), suggesting a potential protective effect against AAA progression.

Metformin also appears to reduce mortality related to AAA repair or rupture, indicating its efficacy in improving outcomes for patients with AAA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Metformin and Abdominal Aortic Aneurysm: A Meta-Analysis. Niu, W., Shao, J., Yu, B., et al.[2022]

Citations

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

Metformin does not reduce inflammation in diabetics with abdominal aortic aneurysm or at high risk of abdominal aortic aneurysm formation. [2018]

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

Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population. [2022]

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

Mechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysms. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Metformin Prescription Associated with Reduced Abdominal Aortic Aneurysm Growth Rate and Reduced Chemokine Expression in a Swedish Cohort. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Association of Metformin and Abdominal Aortic Aneurysm Repair Outcomes. [2022]

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

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Janumet: a combination product suitable for use in patients with Type 2 diabetes. [2019]

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

Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect? [2019]

9. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Efficacy and Cardiovascular Safety of GLP-1 Receptor Analogues. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Glibenclamide and metfoRmin versus stAndard care in gEstational diabeteS (GRACES): a feasibility open label randomised trial. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Association Between Metformin and Abdominal Aortic Aneurysm: A Meta-Analysis. [2022]