Comparison of Pitavastatin Plus Ezetimibe Versus High-Intensity Statin Therapy on Risk of New-Onset Diabetes Mellitus

Inclusion criteria

• Age Requirement:

• Patients aged 18 years or older.

Glycemic Status:

• Patients who are not taking oral hypoglycemic agents (OHAs) and meet all of the following criteria:

• Fasting glucose less than 126 mg/dL.*
• HbA1c less than 6.5%.
• Plasma glucose less than 200 mg/dL after 2 hours during a 75 g oral glucose tolerance test (OGTT).*Note: For fasting glucose, two measurements of 126 mg/dL or greater within 3 months are required for a diagnosis of diabetes.

Cardiovascular Disease:

• Patients with established atherosclerotic cardiovascular disease, defined as having at least one of the following:

• Coronary Heart Disease (CHD):

• Documented history of myocardial infarction (MI).
• History of coronary revascularization.

• 50% stenosis of a major epicardial coronary artery confirmed by cardiac catheterization, computed tomography (CT), or coronary angiography.
• Cerebrovascular Disease:

>History of stroke of atherosclerotic origin.

• History of carotid revascularization.

>≥50% stenosis of the carotid artery confirmed by X-ray angiography, magnetic resonance (MR) angiography, CT angiography, or Doppler ultrasound.

• Symptomatic Peripheral Arterial Disease (PAD):

>Intermittent claudication with an ankle-brachial index (ABI) of 0.90 at rest.

• Intermittent claudication with ≥50% stenosis of a peripheral artery (excluding the carotid artery) confirmed by X-ray angiography, MR angiography, CT angiography, or Doppler ultrasound.
• History of revascularization of peripheral arteries (excluding carotid arteries).
• Lower extremity amputation at or above the ankle due to atherosclerotic disease (excluding trauma or osteomyelitis).

Dietary Requirements:

• Patients must be on a stable diet prior to randomization and able to adhere to the National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Change (TLC) diet or an equivalent throughout the study.

Informed Consent:

• Subjects or their legal representatives must provide written informed consent to the study protocol and clinical follow-up schedule.
• An informed consent form approved by the institutional review board (IRB)/ethics committee of the study site must be signed.

Exclusion criteria

• Patient is pregnant or breastfeeding or of childbearing potential.
• Requires concomitant administration of strong inhibitors of CYP3A4 (itraconazole, ketoconazole, protease inhibitors, erythromycin, clarithromycin, telithromycin, and nefazodone) or CYP2C9 (relative contraindication not dependent on CYP450 statins).
• Chronic kidney disease (eGFR < 30 ml/min/1.73m²) or dialysis-dependent renal failure.
• Uncontrolled hypothyroidism.
• Personal or family history of an inherited muscle disorder.
• History of statin-induced muscle toxicity.
• Alcohol-dependent person.
• Hypersensitivity to statins and ezetimibe.
• Hemodynamic instability at the time of enrollment: cardiogenic shock, refractory ventricular arrhythmia, or congestive heart failure (New York Heart Association class IV) at randomization.
• History of hemorrhagic stroke or intracranial hemorrhage, TIA, or ischemic stroke within the past 6 months.
• Planned surgery requiring discontinuation of statins or ezetimibe within 6 months of randomization.
• Current treatment for active cancer.
• Clinically significant abnormal findings identified at the screening visit, physical examination, laboratory tests, or electrocardiogram that, in the investigator's judgment, may interfere with safe completion of the study.
• Liver disease or biliary obstruction, elevated liver enzymes (ALT or AST > the upper limit of normal) or elevated total bilirubin (total bilirubin > 2 times the upper limit of normal) at screening.
• Life expectancy for noncardiac or cardiac causes < 1 year.
• Unwillingness or inability to comply with the procedures described in this protocol.
• Previously diagnosed with diabetes mellitus and compliant with lifestyle modification and taking oral hypoglycemic agents (OHAs) or insulin.