Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes

Phase 4

Recruiting

• Conditions: Metformin; Prediabetic State; Atherosclerosis
• Interventions: Drug: Placebo; Drug: Metformin XR

• Registration Number: NCT02915198
• Lead Sponsor: VA Office of Research and Development

Brief Summary

This research will help us to learn if the medicine called metformin reduces the risk of death, heart attacks, and/or strokes in Veterans who have pre-diabetes and heart or blood vessel problems.

Detailed Description

CSP #2002 is a multicenter, prospective, randomized, double blind, secondary prevention trial to test the hypothesis that treatment with metformin, compared with placebo, reduces mortality and cardiovascular morbidity in Veterans with pre-diabetes and established atherosclerotic cardiovascular disease. Qualifying patients have pre-diabetes defined by HbA1c, fasting blood glucose, or oral glucose tolerance test criteria; clinically evident coronary, cerebrovascular, or peripheral arterial atherosclerotic cardiovascular disease; and estimated glomerular filtration rate of at least 45 mL/min/1.73 m2; and do not fulfill any exclusion criteria. Patients who are eligible and agree to participate are randomly assigned to treatment with metformin XR (titrated to a maximum dose of 2000 mg daily based on safety and tolerability) or matching placebo. All patients receive counseling on therapeutic lifestyle recommendations.

CSP #2002 had a Pilot Phase trial from 2/2019 to 1/2021 and was approved for the full-scale trial, with Full-scale study launch in 04/2023.

Study Timeline

• Study First Submitted: 2016-09-13
• Study First Submitted QC: 2016-09-22
• Study First Posted: 2016-09-26
• Study Start: 2023-04-03
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-27
• Last Update Posted: 2024-12-30
• Primary Completion: 2029-03-31
• Study Completion: 2029-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 7410

Inclusion Criteria

1. 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.
2. Established atherosclerotic cardiovascular disease: Qualifying participants must have evidence of atherosclerotic disease in at least one of the following vascular beds: coronary, cerebrovascular, or peripheral arterial circulation.

Coronary artery disease is fulfilled by at least one of (1), (2), or (3):

1. History of myocardial infarction at least one month prior to randomization.
2. History of percutaneous coronary intervention or coronary artery bypass surgery at least one month prior to randomization.
3. Angiographic evidence of coronary stenosis of at least 50% in at least two major epicardial coronary arteries.

Cerebrovascular disease is fulfilled by at least one of criteria (1) through (4):

1. Documented prior ischemic stroke (at least one month prior to randomization),
2. Carotid artery stenosis 50% and history of transient ischemic attack or transient ischemic visual symptoms attributable to the identified lesion(s),
3. Asymptomatic carotid stenosis of at least 70% luminal diameter,
4. History of carotid revascularization (surgical or catheter-based).

Peripheral arterial disease: Fulfilled by at least one of the following:

1. History of aorto-iliac or peripheral artery intervention (surgical or catheter based) for limb ischemia, or amputation for limb ischemia,

2. Symptoms of intermittent claudication with ankle:brachial index less than or equal to 0.85.

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

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

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Exclusion Criteria

1. Treatment with metformin or other anti-diabetic medication within 12 months of randomization. Note: In the absence of a diagnosis of diabetes, inpatient treatment with insulin or treatment with an SGLT2 inhibitor (e.g., for heart failure) or a GLP-1 receptor agonist (e.g., for obesity) is not exclusionary.
2. Treatment with systemic glucocorticoids within 3 months of randomization
3. Fasting plasma glucose 140 mg/dL measured between screening and randomization visits, or any plasma glucose 200 mg/dL or HbA1c 7.0% measured within 12 months of randomization.
4. Total CO2 below the local laboratory lower limit of normal on most recent blood chemistry panel
5. Current treatment with cimetidine, vandetanib, or a systemic treatment with a carbonic anhydrase inhibitor.
6. Cirrhosis, active hepatitis, or jaundice at time of randomization, or total bilirubin > 2 times upper limit of normal
7. Binge or heavy alcohol consumption within 6 months of randomization
8. Severe anemia (hemoglobin < 10 g/dL)
9. Prior history of intolerance to metformin
10. Myocardial infarction, coronary revascularization procedure, or stroke within 1 month of randomization
11. Uncontrolled hypertension at screening assessment (systolic blood pressure 180 mm Hg or diastolic blood pressure 110 mm Hg
12. Acute or decompensated congestive heart failure
13. Expected survival less than study duration
14. Participants considered to be unable, unwilling, or unreliable to meet protocol requirements
15. Impaired decision-making capacity, defined by any history of dementia or cognitive impairment
16. Concurrent participation in another research study involving a randomized comparison of drug or device treatments, unless specifically excepted.
17. Pregnant, intent to become pregnant during the trial, or lactating
18. Women of childbearing potential who are not using a highly effective method of contraception

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Time in days to death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina, or symptom-driven coronary revascularization	through study completion, an average of 4.5 years	The primary outcome measure is the time to first occurrence of death, non-fatal myocardial infarction or stroke, hospitalization for unstable angina with objective evidence of acute myocardial ischemia, or coronary revascularization driven by acute or progressive symptoms.

Secondary Outcome Measures

Name	Time	Method
Time in days to Cardiovascular Outcomes	through study completion, an average of 4.5 years	* Time to first occurrence of death, myocardial infarction, or stroke; * Time to first occurrence of a primary endpoint event, peripheral arterial disease event, or hospitalization for congestive heart failure; * Cumulative incidence of all components of the primary endpoint, including recurrent or multiple events in the same participant; * Cumulative incidence and time to first occurrence of each component of the primary outcome measure, peripheral arterial disease events, and hospitalization for congestive heart failure
Time in days to Oncologic Outcome	through study completion, an average of 4.5 years	Time to new or recurrent diagnosis of a malignancy or death from a malignancy
Time in days to Diabetes Outcome	through study completion, an average of 4.5 years	Time to new diagnosis of type 2 diabetes

Trial Locations

Locations (40)

Phoenix VA Health Care System, Phoenix, AZ; 🇺🇸 Phoenix, Arizona, United States

Southern Arizona VA Health Care System, Tucson, AZ; 🇺🇸 Tucson, Arizona, United States

Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR; 🇺🇸 Little Rock, Arkansas, United States

VA Loma Linda Healthcare System, Loma Linda, CA; 🇺🇸 Loma Linda, California, United States

VA Long Beach Healthcare System, Long Beach, CA; 🇺🇸 Long Beach, California, United States

VA Palo Alto Health Care System, Palo Alto, CA; 🇺🇸 Palo Alto, California, United States

VA San Diego Healthcare System, San Diego, CA; 🇺🇸 San Diego, California, United States

VA Greater Los Angeles Healthcare System, West Los Angeles, CA; 🇺🇸 West Los Angeles, California, United States

Rocky Mountain Regional VA Medical Center, Aurora, CO; 🇺🇸 Aurora, Colorado, United States

VA Connecticut Healthcare System West Haven Campus, West Haven, CT; 🇺🇸 West Haven, Connecticut, United States

Bay Pines VA Healthcare System, Pay Pines, FL; 🇺🇸 Bay Pines, Florida, United States

North Florida/South Georgia Veterans Health System, Gainesville, FL; 🇺🇸 Gainesville, Florida, United States

Miami VA Healthcare System, Miami, FL; 🇺🇸 Miami, Florida, United States

Atlanta VA Medical and Rehab Center, Decatur, GA; 🇺🇸 Decatur, Georgia, United States

VA Pacific Islands Health Care System, Honolulu, HI; 🇺🇸 Honolulu, Hawaii, United States

Jesse Brown VA Medical Center, Chicago, IL; 🇺🇸 Chicago, Illinois, United States

Edward Hines Jr. VA Hospital, Hines, IL; 🇺🇸 Hines, Illinois, United States

Iowa City VA Health Care System, Iowa City, IA; 🇺🇸 Iowa City, Iowa, United States

Lexington VA Medical Center, Lexington, KY; 🇺🇸 Lexington, Kentucky, United States

Rehabilitation R&D Service, Baltimore, MD; 🇺🇸 Baltimore, Maryland, United States

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA; 🇺🇸 Boston, Massachusetts, United States

Minneapolis VA Health Care System, Minneapolis, MN; 🇺🇸 Minneapolis, Minnesota, United States

Kansas City VA Medical Center, Kansas City, MO; 🇺🇸 Kansas City, Missouri, United States

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE; 🇺🇸 Omaha, Nebraska, United States

New Mexico VA Health Care System, Albuquerque, NM; 🇺🇸 Albuquerque, New Mexico, United States

Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY; 🇺🇸 New York, New York, United States

Durham VA Medical Center, Durham, NC; 🇺🇸 Durham, North Carolina, United States

Cincinnati VA Medical Center, Cincinnati, OH; 🇺🇸 Cincinnati, Ohio, United States

Louis Stokes VA Medical Center, Cleveland, OH; 🇺🇸 Cleveland, Ohio, United States

Ralph H. Johnson VA Medical Center, Charleston, SC; 🇺🇸 Charleston, South Carolina, United States

VA Portland Health Care System, Portland, OR; 🇺🇸 Portland, Oregon, United States

Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC; 🇺🇸 Columbia, South Carolina, United States

Memphis VA Medical Center, Memphis, TN; 🇺🇸 Memphis, Tennessee, United States

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX; 🇺🇸 Dallas, Texas, United States

Salem VA Medical Center, Salem, VA; 🇺🇸 Salem, Virginia, United States

Michael E. DeBakey VA Medical Center, Houston, TX; 🇺🇸 Houston, Texas, United States

VA Salt Lake City Health Care System, Salt Lake City, UT; 🇺🇸 Salt Lake City, Utah, United States

Hunter Holmes McGuire VA Medical Center, Richmond, VA; 🇺🇸 Richmond, Virginia, United States

Huntington VA Medical Center, Huntington, WV; 🇺🇸 Huntington, West Virginia, United States

Clement J. Zablocki VA Medical Center, Milwaukee, WI; 🇺🇸 Milwaukee, Wisconsin, United States