Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes

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.

Inclusion criteria

• 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.
• 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):

• History of myocardial infarction at least one month prior to randomization.
• History of percutaneous coronary intervention or coronary artery bypass surgery at least one month prior to randomization.
• 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):

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

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

• History of aorto-iliac or peripheral artery intervention (surgical or catheter based) for limb ischemia, or amputation for limb ischemia,
• Symptoms of intermittent claudication with ankle:brachial index less than or equal to 0.85.

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

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

Exclusion criteria

• 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.
• Treatment with systemic glucocorticoids within 3 months of randomization
• Fasting plasma glucose greater than 130 mg/dL measured between screening and randomization visits, or any plasma glucose 180 mg/dL or HbA1c 7.0% measured within 12 months of randomization.
• Total CO2 below the local laboratory lower limit of normal on most recent blood chemistry panel
• Current treatment with cimetidine, vandetanib, or a systemic treatment with a carbonic anhydrase inhibitor.
• Cirrhosis, active hepatitis, or jaundice at time of randomization, or total bilirubin > 2 times upper limit of normal
• Binge or heavy alcohol consumption within 6 months of randomization
• Severe anemia (hemoglobin < 10 g/dL)
• Prior history of intolerance to metformin
• Myocardial infarction, coronary revascularization procedure, or stroke within 1 month of randomization
• Uncontrolled hypertension at screening assessment (systolic blood pressure 180 mm Hg or diastolic blood pressure 110 mm Hg
• Acute or decompensated congestive heart failure
• Expected survival less than study duration
• Participants considered to be unable, unwilling, or unreliable to meet protocol requirements
• Impaired decision-making capacity, defined by any history of dementia or cognitive impairment
• Concurrent participation in another research study involving a randomized comparison of drug or device treatments, unless specifically excepted.
• Pregnant, intent to become pregnant during the trial, or lactating
• Women of childbearing potential who are not using a highly effective method of contraception