Comparison of Low-Intensity Statin Plus Ezetimibe Versus High-Intensity Statin Therapy on Risk of New-Onset Diabetes Mellitus (PROVE-DM)

Study Overview
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Brief Summary
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This study is to evaluating the impact of low-intensity statin plus ezetimibe versus high-intensity statin therapy on risk of new-onset diabetes mellitus in patients with atherosclerotic cardiovascular disease who have prediabetes.

Detailed Description
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The PROVE-DM trial is a multi-center, open-labeled, randomized controlled trial comparing two different lipid lowering strategies in patients with prediabetes and established atherosclerosis. Patients with prediabetes and documented atherosclerosis, either clinical or unequivocal on imaging are eligible for enrollment. The detailed information for inclusion and exclusion criteria is described below in the session 4. Patients meeting inclusion criteria without any exclusion criteria are assessed to be able to tolerate high-intensity statin therapy while achieving the target LDL level (LDL cholesterol < 70 mg/dL for established atherosclerotic cardiovascular disease or LDL cholesterol < 100 mg/dL for mild to moderate coronary artery disease) through a run-in period of 2 to 6 months. (Run in period was set as a screening process to reduce drop-out cases that cannot withstand high-intensity statins or cannot accomplished target LDL levels) Eligible patients will be randomized to high-intensity statin (rosuvastatin 20 mg qd) or low-intensity statin plus ezetimibe (rosuvastatin/ezetimibe 5/10 mg qd). Patients will be followed-up clinically at 6, 12 months and then annually up to 3 years after randomization. Follow-up measurement of DM diagnostic criteria (fasting plasma glucose, plasma Hb A1c, oral glucose tolerance test) and lipid profile is intended to 1) provide evidence of new onset DM, 2) evaluate effectiveness of lowering LDL cholesterol. To ensure the accurate assessment of the clinical outcomes, cardiovascular safety end point (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke), any arterial revascularization, any potential side effects of statin and all-cause mortality were also investigated.

Official Title
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Comparison of Low-Intensity Statin Plus Ezetimibe Versus High-Intensity Statin Therapy on Risk of New-Onset Diabetes Mellitus in Prediabetic Patients With Atherosclerotic Cardiovascular Disease

Conditions
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Pre Diabetes, ASCVD

Intervention / Treatment
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* Drug: high-intensity statin arm
* Drug: low-intensity statin plus ezetimibe


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women between the ages of 18 and 75 years who have prediabetes -Prediabetes consists of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or HbA1c IFG: fasting plasma glucose (FPG) 100 to 125 mg/dL IGT: 2 hours post-load glucose on the 75g OGTT (oral glucose tolerance test) 140 to 199 mg/dL HbA1c: 5.7 to 6.4% Patient requiring high-intensity statin due to high risk of a future cardiovascular event if at least one of the following criteria is present via patient history, physical examination, or medical records at the time of screening (Clinically documented ASCVD) acute coronary syndrome (MI or unstable angina) stable angina coronary revascularization (PCI, CABG, and other arterial revascularization procedure) stroke or TIA peripheral arterial disease (<0.9 performed by a vascular lab or angiogram (including CTA) showing ≥ 50%) Unequivocally documented ASCVD on imaging significant plaque on coronary angiography on CT (mild, moderate, severe coronary artery disease) significant plaque on carotid ultrasound (mild, moderate, severe carotid disease) Patients who have never taken a statin or who do not have problems adhering to statin therapy Patient must have been on a stable diet prior to randomization and willing to follow the NCEP (national Cholesterol Education Program) TLC (therapeutic lifestyle changes) diet, or equivalent diet, throughout the study. The patient or guardian agrees to the study protocol and the schedule of clinical follow-up, and provides informed, written consent, as approved by the appropriate Institutional Review Board/Ethical Committee of the respective clinical site. Exclusion Criteria: Patient's pregnant or breast-feeding or child-bearing potential. Concomitant administration of potent 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 hereditary muscular disorders. History of muscular toxicity with a statin Alcoholism. Hypersensitivity to any of statin and ezetimibe. Hemodynamic unstable conditions at the time of inclusion: cardiogenic shock at the time of randomization, refractory ventricular arrhythmias, or congestive heart failure (New York Heart Association class IV). Any history of hemorrhagic stroke or intracranial hemorrhage within the past 6 months Any surgery requiring discontinuation of statin and/or ezetimibe is planned within 6 months after randomization A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in the past 3 years or current treatment for the active cancer. Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the Investigator, would preclude safe completion of the study. Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST > 3 times upper limit of normal) or (Total bilirubin> 2 times upper limit of normal). Life expectancy < 1 years for any non-cardiac or cardiac causes Unwillingness or inability to comply with the procedures described in this protocol. Patients who are actively participating in another drug or device investigational study, which have not completed the primary endpoint follow-up period. People who have previously been diagnosed with diabetes and are taking lifestyle modification and oral hypoglycemic agent (OHA) or insulin (In woman, gestational diabetes is included)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: high-intensity statin arm<br>(high-intensity statin arm): rosuvastatin 20 mg PO qd, once daily | Drug: high-intensity statin arm<br>* •high-intensity statin strategy (standard arm): rosuvastatin 20 mg PO qd, once daily<br>|
| Active Comparator: low-intensity statin plus ezetimibe arm<br>(low-intensity statin plus ezetimibe arm ): rosuvastatin 5mg /ezetimibe 10mg PO qd), once daily | Drug: low-intensity statin plus ezetimibe<br>* •low-intensity statin plus ezetimibe strategy (experimental arm): rosuvastatin 5mg /ezetimibe 10mg PO qd), once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with New-onset-DM | New onset DM was defined on the the basis of the American Diabetes association guideline if two abnormal test results of following criteria are existed from the same sample or in two separate test samples. fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours OR 2 hour plasma glucose during a 75 g oral glucose tolerance test (OGTT) ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water OR HbA1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP (National Glycohemoglobin Standardization Program) certified and standardized to the DCCT (Diabetes Control and Complication Trial) assay. | 36months after randomization | 
| Number of Participants with death | Major adverse cardiac events are defined as all-cause death | 36months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite cardiovascular safety | death from cardiovascular cause, non fatal myocardial infarction of nom fatal stroke | 36months after randomization | 
| Any arterial revascularization | Any arterial revascularization (carotid, coronary aorta or peripheral artery) Any arterial revascularization (carotid, coronary aorta or peripheral artery) | 36months after randomization | 
| Any potential side effect | Any potential side effect | 36months after randomization | 
| Each component of the diabetes-mellitus diagnosis criteria | Each component of the diabetes-mellitus diagnosis criteria | 36months after randomization | 
| All cause mortality | All cause mortality | 36months after randomization |