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 patients with pre-diabetes and established
atherosclerotic cardiovascular disease. Qualifying patients have pre-diabetes defined by
HbA1c, fasting blood glucose, and/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.

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. At least one of these criteria must be met in the absence
of diabetic treatment. For a participant to qualify with pre-diabetes on basis of one
of these criteria, the results must have been obtained per the allowable time
intervals indicated in Table 2. Any or all qualifying laboratory values may have been
obtained either in a VA or a non-VA laboratory, but in either case the laboratory
source documents, including date(s) of testing and test results must be available and
data recorded on the appropriate case report form.

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.

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

1. History of myocardial infarction at least one month prior to Randomization:
Fulfilled by (a), (b), or both:

(a) Hospital summary or notes recording diagnosis of myocardial infarction
(b) At least two of the following:

i) pathologic Q-waves (and/or pathologic R wave in lead V1) consistent with myocardial
infarction; ii) myocardial perfusion abnormality consistent with infarction; or iii)
regional wall motion abnormality consistent with infarction. (2) History of
percutaneous coronary intervention or coronary artery bypass surgery at least one
month prior to Randomization (3) Angiographic evidence of significant coronary
stenosis: At least 50% luminal stenosis in at least two major epicardial coronary
arteries and/or their major branches (left main, left anterior descending and/or
principal diagonal branches, left circumflex and/or principal obtuse marginal
branches, or right and/or posterior descending or posterolateral branch).

b) Cerebrovascular disease: Fulfilled by at least one of criteria (1) through (4):

1. Documented prior ischemic stroke (at least one month prior to Randomization) based
upon at least one of the following:

1. stroke documented in hospital discharge summary or neurologic consultation note,
not including subarachnoid or subdural hemorrhage;

2. neuroimaging study consistent with prior ischemic stroke

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 70%

4. History of carotid revascularization (surgical or catheter-based)

c) Peripheral arterial disease: Fulfilled by (1), (2), or both:

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 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. Related to glucometabolic state:

a) Treatment with metformin or other anti-diabetic medication within 12 months of
randomization.

b) Treatment with systemic glucocorticoids within 3 months of randomization (due to
potential effect on plasma glucose and HbA1c levels).

c) 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.

2. Related to safety or tolerability:

a) Metabolic acidosis (total CO2 below the local laboratory lower limit of normal on
most recent blood chemistry panel)

b) Current treatment with cimetidine, vandetanib, or a systemic carbonic anhydrase
inhibitor (topiramate, acetazolamide, methazolamide, dichlorphenamide, or zonisamide).
Use of ophthalmic carbonic anhydrase inhibitors is not exclusionary.

c) Cirrhosis, active hepatitis, or jaundice at time of randomization, or total
bilirubin > 2 times upper limit of normal on most recent laboratory study

d) Binge or heavy alcohol consumption within 6 months of randomization. Binge drinking
is defined by consumption of 5 or more alcoholic drinks for men or 4 for women within
2 hours. Heavy drinking is defined by consumption of 5 or more alcoholic drinks on one
occasion, occurring 5 or more times in a month.

e) Severe anemia (hemoglobin < 10 g/dL) on screening or most recent laboratory testing

f) Prior history of intolerance to metformin

3. Related to likelihood of non-modifiable events:

a) Myocardial infarction, coronary revascularization procedure (PCI or CABG), or
stroke within 1 month of randomization

b) Uncontrolled hypertension at screening assessment (systolic blood pressure 180 mm
Hg or diastolic blood pressure 110 mm Hg

c) Acute or decompensated congestive heart failure

4. Related to prognosis, reliability, ethics, or data validity:

1. Expected survival less than study duration

2. Participants considered to be unable, unwilling, or unreliable to meet protocol
requirements

3. Impaired decision-making capacity, defined by any history of dementia or
cognitive impairment

4. Concurrent participation in another research study involving a randomized
comparison of drug or device treatments, unless specifically excepted by CSP.

5. Female participants

1. Pregnant or intent to become pregnant during the trial

2. Lactating

3. Women of childbearing potential who are not using a highly effective method of
contraception