Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes

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 100-125mg/dL; or a 2-hour plasma glucose level of 140-199 mg/dL following a 75 g glucoseload oral glucose tolerance test.

2. Established atherosclerotic cardiovascular disease: Qualifying participants musthave evidence of atherosclerotic disease in at least one of the following vascularbeds: 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 atleast one month prior to randomization.

3. Angiographic evidence of coronary stenosis of at least 50% in at least two majorepicardial 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 transientischemic 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 catheterbased) for limb ischemia, or amputation for limb ischemia,

2. Symptoms of intermittent claudication with ankle:brachial index less than or equalto 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.

Exclusion Criteria:

1. Treatment with metformin or other anti-diabetic medication within 12 months ofrandomization. Note: In the absence of a diagnosis of diabetes, inpatient treatmentwith insulin or treatment with an SGLT2 inhibitor (e.g., for heart failure) or aGLP-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 randomizationvisits, or any plasma glucose 200 mg/dL or HbA1c 7.0% measured within 12 months ofrandomization.

4. Total CO2 below the local laboratory lower limit of normal on most recent bloodchemistry panel

5. Current treatment with cimetidine, vandetanib, or a systemic treatment with acarbonic anhydrase inhibitor.

6. Cirrhosis, active hepatitis, or jaundice at time of randomization, or totalbilirubin > 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 1month of randomization

11. Uncontrolled hypertension at screening assessment (systolic blood pressure 180 mm Hgor 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 protocolrequirements

15. Impaired decision-making capacity, defined by any history of dementia or cognitiveimpairment

16. Concurrent participation in another research study involving a randomized comparisonof 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 ofcontraception