Metformin for Prediabetes

(VA-IMPACT Trial)

Recruiting in Palo Alto (17 mi)

+38 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: VA Office of Research and Development

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

Disqualifiers: Diabetes, Cirrhosis, Hypertension, others

Prior Safety Data

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing whether metformin can lower the risk of death, heart attacks, and strokes in people with pre-diabetes and heart or blood vessel issues. Metformin is a drug that helps control blood sugar levels and has been used to treat type 2 diabetes mellitus for more than 60 years. The study involves patients who have pre-diabetes and existing heart or blood vessel problems, aiming to see if metformin can provide additional health benefits.

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.

Is metformin safe for humans?

Metformin, including its extended-release versions like Glucophage XR and Glumetza, has been shown to be well-tolerated in clinical trials for type 2 diabetes, with no increase in adverse events at higher doses. However, it should not be used by people with kidney problems. ^{1 2 3 4 5}

How does the drug Metformin XR differ from other treatments for prediabetes?

Metformin XR is unique because it is a prolonged-release form of metformin, which helps to lower blood sugar levels gradually and is well-tolerated with fewer gastrointestinal side effects. It is specifically used to manage prediabetes by normalizing fasting plasma glucose levels in a significant portion of patients, aligning with current guidelines for prediabetes management. ^{2 6 7 8 9}

Research Team

Gregory G. Schwartz, PhD MD

Principal Investigator

Rocky Mountain Regional VA Medical Center, Aurora, CO

Eligibility Criteria

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

You have very low levels of hemoglobin in your blood.

Trial Timeline

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

Treatment Details

Interventions

• Metformin XR (Biguanide)
• Placebo (Drug)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

Findings from Research

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]

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]

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]

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]

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]

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]

References

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

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. [2013]

2. England pubmed.ncbi.nlm.nih.gov

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

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

Metformin extended release for the treatment of type 2 diabetes mellitus. [2019]

4. Switzerland 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. [2020]

5. England 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. [2022]

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

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

7. India pubmed.ncbi.nlm.nih.gov

Drug therapy in prediabetes. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Observational study of the efficacy of prolonged-release metformin in people with prediabetes. [2020]

9. United States 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. [2021]