Metformin for Prediabetes

(VA-IMPACT Trial)

Recruiting at 38 trial locations

Overseen By Kevin Gropp

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must not be taking: Metformin, Glucocorticoids, Cimetidine, others

Disqualifiers: Diabetes, Cirrhosis, Hypertension, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4.5 years

7410 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether metformin, a drug used to control blood sugar levels, can reduce the risk of death, heart attacks, and strokes in Veterans with pre-diabetes and cardiovascular issues. Participants will receive either metformin or a placebo (a pill with no active medicine). The trial suits individuals with pre-diabetes and heart problems, such as a history of heart attack or stroke, who have not recently taken metformin or similar medications. As a Phase 4 trial, this research aims to understand how this already FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as metformin or other anti-diabetic drugs, within 12 months before joining. You also cannot be on cimetidine, vandetanib, or systemic carbonic anhydrase inhibitors. If you're on these medications, you may need to stop them to participate.

What is the safety track record for Metformin XR?

Studies have shown that metformin XR is generally well-tolerated. Research indicates it causes fewer stomach issues than the regular version of metformin, leading to less nausea or diarrhea. Metformin XR's safety profile is similar to other types of metformin, but it is gentler on the stomach. The American Diabetes Association recommends metformin for people with prediabetes, demonstrating its trustworthiness for long-term use. Overall, metformin XR is considered a safe choice for managing blood sugar levels, with a strong track record in past research. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Most treatments for prediabetes involve lifestyle changes, such as diet and exercise, or medications like metformin in its standard form. However, Metformin XR, the extended-release version of metformin, offers a unique advantage. Unlike the standard metformin, which requires multiple doses throughout the day, Metformin XR simplifies the regimen by allowing a once-daily dosage. This can improve adherence and make it easier for people to stick with their medication plan. Researchers are excited about this treatment because it promises similar benefits to regular metformin but with greater convenience and potentially fewer side effects.

What is the effectiveness track record for metformin in reducing the risk of death, heart attacks, and strokes in patients with prediabetes?

Research has shown that metformin can help people with prediabetes lower their risk of developing diabetes. One study found that metformin reduced the risk of diabetes by 31% over three years. In this trial, participants will receive either the extended-release version, Metformin XR, or a placebo. Metformin XR functions like the regular version but may be easier to take. Blood sugar levels typically decrease within the first few weeks of starting metformin. This suggests that metformin may also help control blood sugar in people with heart or blood vessel problems. ^{3 6 7 8 9}

Who Is on the Research Team?

Gregory G. Schwartz, PhD MD

Principal Investigator

Rocky Mountain Regional VA Medical Center, Aurora, CO

Are You a Good Fit for This Trial?

This trial is for adults with pre-diabetes (HbA1c between 5.7% and 6.5%, or specific fasting glucose levels) who also have a history of heart disease, such as past heart attacks or strokes, and evidence of atherosclerosis. They should not have used metformin recently, be pregnant, or have severe health issues like liver disease, uncontrolled high blood pressure, recent heart events within the last month.

Inclusion Criteria

Informed consent has been fully executed, and participant agrees to study procedures

My blood sugar levels indicate I have pre-diabetes.

My kidneys work well enough (filtration rate is okay).

Exclusion Criteria

Your recent blood test showed a lower level of CO2 than what is considered normal at the local laboratory.

You have very low levels of hemoglobin in your blood.

You have been drinking a lot of alcohol or binge drinking within the past 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metformin XR or placebo with stepwise titration to a maximum dose of 2000 mg daily

4.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Metformin XR
• Placebo

Trial Overview

The study tests if Metformin XR can reduce the risk of death or cardiovascular events like heart attacks and strokes in people with pre-diabetes and existing heart problems compared to a placebo (a pill without active medication). Participants will randomly receive either Metformin XR or placebo.

How Is the Trial Designed?

Group I: Metformin Experimental Treatment 1 Intervention

Participants receive initial treatment with metformin XR 500 mg 1 tablet daily, with stepwise titration to a maximum dose of 2000 mg (4 tablets) daily.

Group II: Placebo Placebo Group 1 Intervention

Participants receive initial treatment with 1 tablet daily of placebo (for metformin XR), with stepwise titration to a maximum of 4 tablets daily.

Metformin XR is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Glucophage for:

• Type 2 Diabetes Mellitus

Approved in European Union as Glucophage for:

• Type 2 Diabetes Mellitus

Approved in Canada as Glumetza for:

• Type 2 Diabetes Mellitus

Approved in Japan as Riomet for:

• Type 2 Diabetes Mellitus

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Glumetz (M-ER) is a newly approved extended-release formulation of metformin that provides effective and sustained glycemic control with once-daily dosing, showing similar bioavailability to immediate-release metformin taken twice daily.

In clinical trials lasting 24 weeks, M-ER demonstrated good efficacy and was well tolerated, with continued glycemic control maintained in an additional 24-week open-label extension study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. Schwartz, SL., Gordi, T., Hou, E., et al.[2013]

Patients with impaired fasting glucose and impaired glucose tolerance are classified as having 'prediabetes', which significantly increases their risk of developing diabetes and cardiovascular diseases.

Various medications, including metformin and glitazones, have shown effectiveness in improving blood sugar levels in prediabetes, but none are currently recommended by professional organizations for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug therapy in prediabetes. Mukhopadhyay, P., Chowdhury, S.[2013]

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]

In two studies involving a total of 982 patients, metformin XR significantly reduced HbA1C levels compared to placebo, demonstrating its efficacy in improving glycemic control in patients with inadequate management despite diet and exercise.

A clear dose-response relationship was observed, with higher doses of metformin XR leading to greater reductions in HbA1C, and the medication was well tolerated, with minimal withdrawals due to gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Fujioka, K., Brazg, RL., Raz, I., 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]

Once-weekly GLP-1 receptor agonists (albiglutide, dulaglutide, exenatide ER, and semaglutide) significantly reduce glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight compared to placebo, indicating their efficacy in managing type 2 diabetes.

Among these, semaglutide showed the most substantial reductions in HbA1c, FPG, and body weight compared to exenatide ER, suggesting it may be the most effective option among the once-weekly treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Efficacy of Once-weekly Glucagonlike Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes. Bailey, TS.[2019]

In a study of 686 subjects with prediabetes, prolonged-release metformin (metformin XR) effectively reduced fasting plasma glucose levels, normalizing them in 43% of participants after 12 weeks.

Metformin XR was well tolerated, with gastrointestinal side effects being the most common, supporting its use as a safe treatment option for managing prediabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observational study of the efficacy of prolonged-release metformin in people with prediabetes. Hostalek, U., Zilahi, Z.[2020]

GLP-1 receptor agonists, while effective in reducing weight and postprandial blood glucose levels, do not significantly lower HbA1c levels compared to insulin glargine, indicating similar efficacy in glycemic control.

Insulin glargine was found to be more effective in reducing fasting blood glucose but was associated with a higher incidence of nocturnal hypoglycemia and influenza, while GLP-1 receptor agonists had more gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 receptor agonists versus insulin glargine for type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Li, WX., Gou, JF., Tian, JH., et al.[2021]

Semaglutide, an oral antidiabetic agent approved by the US-FDA, showed the highest efficacy in lowering HbA1c levels in Type 2 Diabetes Mellitus patients, with a significant reduction of 1.6% at a dose of 1.0 mg (p < 0.0001).

The safety profiles of the newer antidiabetic agents were generally similar to placebo, with no fatal adverse events reported; however, gastrointestinal issues and hypoglycemic events were the most common side effects, with alogliptin having the least frequency of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients. Palanisamy, S., Yien, ELH., Shi, LW., et al.[2020]

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