Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes

• Status: Active, not recruiting
• Trial end date: 2024-08-21
• Target enrollment: 0
• Participant gender: All

Summary

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

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: VA Office of Research and Development
• Treatments: Metformin

Criteria

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