What side effects are associated with this type of intervention?

Metformin, commonly used to manage type 2 diabetes, can cause gastrointestinal side effects such as nausea, diarrhea, and abdominal discomfort. It may also lead to vitamin B12 deficiency with long-term use. Statins, another common treatment for atherosclerosis, can cause muscle pain, liver enzyme abnormalities, and, rarely, rhabdomyolysis. PCSK9 inhibitors, used to lower LDL cholesterol, may cause injection site reactions, flu-like symptoms, and neurocognitive issues. These treatments are generally well-tolerated but require monitoring for potential side effects.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of atherosclerosis and related cardiovascular conditions, particularly in patients with diabetes. Metformin, while primarily used for glycemic control, is being studied for its potential to reduce cardiovascular events. Other approved treatments include statins (e.g., atorvastatin, simvastatin) which lower cholesterol levels and reduce cardiovascular risk, and GLP-1 receptor agonists (e.g., liraglutide, semaglutide) which improve glycemic control and have shown cardiovascular benefits. Additionally, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin) have been approved for their dual role in glycemic control and cardiovascular risk reduction.

What other types of research exist?

Promising alternatives to Metformin for atherosclerosis patients include Sodium-Glucose Co-Transporter 2 inhibitors (SGLT2-i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA). SGLT2-i reduce cardiovascular events and improve glycemic control by promoting glucose excretion through urine. GLP1-RA improve insulin secretion, reduce appetite, and have shown benefits in reducing cardiovascular events. Both classes have demonstrated efficacy in cardiovascular outcomes trials.

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Biguanide

Metformin for Prediabetes (VA-IMPACT Trial)

Phase 4

Recruiting

Research Sponsored by VA Office of Research and Development

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Pre-diabetes: This condition is fulfilled by HbA1c of at least 5.7%, but less than 6.5%; or two measurements of fasting plasma glucose (on separate days) of 100-125 mg/dL; or a 2-hour plasma glucose level of 140-199 mg/dL following a 75 g glucose load oral glucose tolerance test.

Renal function: Estimated glomerular filtration rate at least 45 mL/min/1.73 m2.

Must not have

Cirrhosis, active hepatitis, or jaundice at time of randomization, or total bilirubin > 2 times upper limit of normal

Prior history of intolerance to metformin

Timeline

Screening 3 weeks

Treatment Varies

Follow Up through study completion, an average of 4.5 years

Awards & highlights

Pivotal Trial

Drug Has Already Been Approved

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Metformin may cause side effects such as digestive upset (nausea, diarrhea), vitamin B12 deficiency over time which could lead to anemia or nerve damage if untreated, and rarely a serious condition called lactic acidosis.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My blood sugar levels indicate I have pre-diabetes.

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

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I have a history of heart issues, including a heart attack, surgery, or significant artery blockage.

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My blood sugar levels indicate I have pre-diabetes.

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

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I have heart or blood vessel disease due to plaque buildup.

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I have had surgery or a procedure to open my carotid artery.

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I have heart or blood vessel disease due to plaque buildup.

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I have a narrowed carotid artery and have had symptoms like a mini-stroke.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have cirrhosis, active hepatitis, jaundice, or a bilirubin level more than twice the normal limit.

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I have had a bad reaction to metformin before.

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I am not using a highly effective birth control method.

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I am currently taking cimetidine, vandetanib, or a medication that affects body acidity.

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My blood sugar levels are within the specified limits.

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I have a history of dementia or cognitive issues affecting my decision-making.

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I have worsening heart failure symptoms.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ through study completion, an average of 4.5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~through study completion, an average of 4.5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and through study completion, an average of 4.5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Time in days to death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina, or symptom-driven coronary revascularization

Secondary study objectives

Time in days to Cardiovascular Outcomes

Time in days to Diabetes Outcome

Time in days to Oncologic Outcome

Side effects data

From 2016 Phase 4 trial • 532 Patients • NCT02252965

14%

Diarrhoea

Abdominal Distension

Nausea

Dizziness

Abdominal Discomfort

Gastrooesophageal Reflux Disease

Vomiting

Hepatic Function Abnormal

Decreased Appetite

Abdominal Pain Upper

Abdominal Pain

Constipation

Upper Respiratory Tract Infection

Hyperhidrosis

Fatigue

Hepatic Steatosis

Dyslipidaemia

Blood uric Acid Increased

Urinary tract Infection

Palpitations

Protein Urine Present

Hyperuricaemia

Hypoglycaemia

Dyspepsia

Frequent Bowel Movements

Hyperlipidaemia

Asthenia

100%

80%

60%

40%

20%

Study treatment Arm

Metformin IR

Metformin XR

Metformin IR to XR

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Drug Has Already Been Approved

The FDA has already approved this drug, and is just seeking more data.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: MetforminExperimental Treatment1 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: PlaceboPlacebo Group1 Intervention

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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Metformin XR

2013

Completed Phase 4

~9220

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for atherosclerosis, such as metformin, work by decreasing hepatic glucose production, reducing intestinal absorption of glucose, and improving insulin sensitivity. These mechanisms help lower blood glucose levels, which is crucial for preventing endothelial dysfunction and the formation of atherosclerotic plaques. Additionally, treatments like statins reduce LDL cholesterol and have anti-inflammatory effects, further preventing plaque formation and progression. Managing blood glucose and lipid levels is essential for reducing the risk of cardiovascular events in atherosclerosis patients.

Effects of tolbutamide and glyburide on glucose and acetate incorporation into aortic lipids of the dog.